PMID: 33301989

A PIK3CG variant in the catalytic domain is a risk factor for some infection-induced heart issue?

PMID:38485815

Gene:CTLA4

HGNC:2505

Case#: 88 ITP patients

DiseaseAssertion: Immune thrombocytopenia

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Real-Time PCR with sequence-specific primers was used to assess the CTLA-4 genotype

GenotypingMethod: Real-Time PCR with sequence-specific primers was used to assess the CTLA-4 genotype.

PreviouslyPublished: No

Variant: NM_005214.5:c.49A>G

ClinVar: 16921

CAID: CA126974

gnomAD: 0.6450 https://gnomad.broadinstitute.org/variant/2-203867991-A-G?dataset=gnomad_r4

Variant: NC_000002.12:g.203874196G>A

ClinVar: 16922

CAID: CA11297605

gnomAD: 0.6078 https://gnomad.broadinstitute.org/variant/2-203874196-G-A?dataset=gnomad_r3

PMID:38634985

Gene:PIK3CD

HGNC:8977

[[AD_VCEP_Annotation_Protocol_Updated.pdf]]

Case#: 42 Chinese APDS1 patients (27 males and 15 females)

DiseaseAssertion: activated PI3Kδ syndrome 1(APDS1)

FamilyInfo: 42 patients from 41 different families in China (P3 and P11 were from one family)

CasePresentingHPOs: HP:0002205(Recurrent respiratory infections) HP:0002110(Bronchiectasis) HP:00027168(Lymphadenopathy) HP:0001744(Splenomegaly) HP:0002240(Hepatomegaly) HP:0002960(Autoimmunity) HP:0003496(Increased circulating IgM level) HP:0004315(Decreased circulating IgG level) HP:0003237(Increased circulating IgG level) HP:0003212(Increased circulating IgE level) HP:0002720(Decreased circulating IgA level) HP:0040218(Reduced natural killer cell count) HP:0005403(T lymphocytopenia) HP:0005407(Decreased proportion of CD4-positive helper T cells)

CaseHPOFreeText: Table 1 contains information of 42 patients. Immunological phenotype of cohort is summarized in Table 2.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole-exome sequencing

GenotypingMethod: Whole-exome sequencing

PreviouslyPublished: No

Variant: NM_005026.5:c.3061G>A p.E1021K

ClinVar: 88675

CAID: CA577192

gnomAD: 8.475e-7 https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Variant: NM_005026.5(PIK3CD):c.3074A>G p.Glu1025Gly

ClinVar: 422410

CAID: CA16617216

gnomAD: Variant is not present in gnomAD data

Variant: NM_005026.5(PIK3CD):c.1574A>G (p.Glu525Gly)

ClinVar: 582515

CAID: CA338303813

gnomAD: Variant is not present in gnomAD data

Variant: NM_005026.5(PIK3CD):c.1570T>A p.Tyr524Asn

ClinVar: Not present in ClinVar

CAID: CA338303802

gnomAD: Variant is not present in gnomAD data

Case#: P5

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (2 m), otitis media, bronchiectasis (6 y), Gastroenteritis, Lymphadenomegaly, splenomegaly, hepatomegaly, Oblique inguinal hernia, urinary tract infection, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor, HSCT.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P6

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Skin pigmentation, Recurrent respiratory tract infections (1 y), otitis media, Lymphadenomegaly, splenomegaly, hepatomegaly, Failure to thrive, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P7

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (4 y), bronchiectasis, otitis media, eardrum perforation, hearing loss, Gastroenteritis, Lymphadenomegaly, splenomegaly, hepatomegaly, ITP, Conjunctivitis, failure to thrive, anti-infection prophylaxis, IVIG, mTOR inhibitor

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P8

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Diarrhea, No sinopulmonary infections, Chronic diarrhea, Lymphadenomegaly, splenomegaly, anti-infection prophylaxis, IVIG.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P9

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Diarrhea, Recurrent respiratory tract infections (1.5 y), otitis media, bronchiectasis (5 y), pleural effusion, Chronic diarrhea, Lymphadenomegaly, splenomegaly, hepatomegaly, Congenital patent foramen ovale, hypoproteinemia, failure to thrive, nasosinusitis, mastoiditis, thick corpus callosum, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P11

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Diarrhea, Recurrent respiratory tract infections (1 y), bronchiectasis (9 y), Chronic diarrhea and rectocolitis, Lymphadenomegaly, splenomegaly, hepatomegaly, Hypothyroidism and thrombocytopenia, Failure to thrive, nasosinusitis, mastoiditis, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor, HSCT

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P12

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (3 m), Lymphadenomegaly, splenomegaly, hepatomegaly, AIHA, Leukoencephalopathy, failure to thrive, mastoiditis, demyelination, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P13

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (2.5 y), bronchiectasis, Lymphadenomegaly, splenomegaly, hepatomegaly, Nasosinusitis, mastoiditis, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P14

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (3 y), pneumothorax, Lymphadenomegaly, splenomegaly, anti-infection prophylaxis, HSCT.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P15

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (8 m), bronchiectasis, Lymphadenomegaly, splenomegaly, hepatomegaly, Urinary tract infection, anti-infection prophylaxis, IVIG, mTOR inhibitor, HSCT.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P16

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Splenomegaly, Recurrent respiratory tract infections (3 y), Chronic diarrhea and colonic ulcers, Lymphadenomegaly, splenomegaly, hepatomegaly, IBD, anti-infection prophylaxis, IVIG.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P18

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (6 m), bronchiectasis (9 y), otitis media, hearing loss, Chronic diarrhea and hematochezia, Lymphadenomegaly, splenomegaly, ITP, IBD, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor, HSCT.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P19

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (8 m), bronchiectasis (12 y), Small intestinal ulcers, proctitis, colitis, Lymphadenomegaly, splenomegaly, hepatomegaly, IBD, Ventricular septal defect, failure to thrive, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P20

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (3 m), bronchiectasis (12 y), otitis media, Lymphadenomegaly, splenomegaly, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P21

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (3 m), otitis media, hearing loss, Lymphadenomegaly, splenomegaly, hepatomegaly, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P22

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Diarrhea, Recurrent respiratory tract infections (2 y), bronchiectasis (6 y), Proctitis, colitis, intestinal obstruction, Lymphadenomegaly, splenomegaly, IBD, Nasosinusitis, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P23

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Diarrhea, No sinopulmonary infections, Duodenitis and colitis, Lymphadenomegaly, splenomegaly, hepatomegaly, Hypothyroidism and IBD, Dysmyelination, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor, HSCT.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P24

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (2 w), otitis media, Esophagitis, gastritis, duodenitis, colitis, rectitis, Lymphadenomegaly, hepatomegaly, IBD, Atrial septal defect, nasosinusitis, mastoiditis, anti-infection prophylaxis, IVIG, mTOR inhibitor, HSCT.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P25

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (1 m), bronchiectasis (14 y), Lymphadenomegaly, splenomegaly, hepatomegaly, SLE and lupus nephritis, Failure to thrive, nasosinusitis, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P26

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Axillary lymph node enlargement, Recurrent respiratory tract infections (2.5 y), bronchiectasis (4 y), Lymphadenomegaly, splenomegaly, hepatomegaly, Hematuria, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P27

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (2 y), bronchiectasis (7 y), otitis media, hearing loss, Colon ulcer, gastritis, enteritis, Lymphadenomegaly, splenomegaly, hepatomegaly, IBD, Hypoalbuminemia, nasosinusitis, mastoiditis, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P28

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (3 m), otitis media, Lymphadenomegaly, splenomegaly, BCGitis, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P29

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (4 m), otitis media, Lymphadenomegaly, splenomegaly, hepatomegaly, Thrombocytopenia, Mastoiditis, arachnoid cyst, dysmyelination, nasosinusitis, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P30

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Hematochezia, Recurrent respiratory tract infections (6 y), Hematochezia, gastritis, colitis, Lymphadenomegaly, splenomegaly, IBD, Urinary tract infection, chronic recurrent parotitis, mastoiditis, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P31

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Abdominal pain, No sinopulmonary infections, Intussusception, peritonitis, intestinal obstruction, acute peritonitis, acute appendicitis, multiple ileal polyps, Lymphadenomegaly, splenomegaly, hepatomegaly, Inguinal hernia, nasosinusitis, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P32

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (1 y), bronchiectasis (10 y), Gastrointestinal bleeding, suppurative appendicitis, coloproctitis, duodenitis, Lymphadenomegaly, splenomegaly, hepatomegaly, IBD, Severe malnutrition, Grade I AV block, conjunctivitis, hypertension, osteoporosis, failure to thrive, nasosinusitis, mastoiditis, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor, HSCT.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P33

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Hematochezia, Recurrent respiratory tract infections (4 y), Chronic gastritis and colitis, duodenitis, Lymphadenomegaly, splenomegaly, hepatomegaly, IBD, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor, HSCT.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P34

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (3 m), bronchiectasis, Lymphadenomegaly, splenomegaly, Arthritis, Nasosinusitis, anti-infection prophylaxis, IVIG, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

HGVS: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

PMID: 35021606

Gene: PIK3CD

HGNC: 8977

Note: This paper records a cohort in which 33% of PTCL-EBV tumors (3/9 tested, Table S12) had mutations in PIK3CD (specific mutations not reported).

PMID: 32681977

Gene: PIK3CD

HGNC: 8977

Case#: Lougaris_2020_case, male, 12 yo (onset), origin in romania

DiseaseAssertion: APDS

FamilyInfo: non-consanguinous

CasePresentingHPOs: rash HP:0000988 pruritus HP:0000989 arthritis HP:0001369 splenomegaly HP:0001744 fever HP:0001945 lymphoma HP:0002665 arthralgias HP:0002829 increased ferritin HP:0003281 hepatitis HP:0012115 desquamation HP:0040189 malaise HP:0033834 increaased effector memory CD4 T cells HP:0025625

CaseHPOFreeText: increased AST, lymphadenomegaly, presence of rare hemophagocytes in bone marrow, elevated effector memory CD8 T cells, impaired peripheral B cell distribution, increased glucose metabolism in lymph nodes and spleen, increased IgG-positive plasma cells in the germinal centre and in the interfollicular area

CaseNotHPOs: EBV HP:0031693 Cytomegalovirus (CMV) HP:0031692 Abnormal NK count HP:0040089

CaseNotHPOFreeText: Herpes virus type I and II, Human herpes virus 8 (HHV8)

CasePreviousTesting:

GenotypingMethod: NGS

PreviouslyPublished: NR

Variant: c.323G > T: p.R108L

ClinVarID: 636973

CAID:

gnomAD: 0.00002823 Admixed American (1/35426)

SupplementalData:

Note: rash followed by desquamation - possible eczma?

Experimental Assay

PMID: 33080915

Gene: PIK3CD

HGNC: 8977

PMID: 27596086

Gene: PIK3CD

HGNC: 8977

Case#: Hui_2016, female, 2 yo (presentation), origin NR

DiseaseAssertion: APDS

FamilyInfo: variants verified in patient's parents, found to be de novo. It is unclear if case 2 and case 4 are related or unrelated.

CasePresentingHPOs: recurrent respiratory infections, enlargement of lymph node, hepatosplenomegaly, decreased number of native CD4 + T cells, inverted CD4 + /CD8 + T cell ratio and increased IgM, decreased IgA, decreased IgG,

HP:0002205, HP:0002716, HP:0001433, HP:0002720, HP:0032218, HP:0033222, HP:0002720, HP:0003496

CaseHPOFreeText: cytomegalovirus (CMV) or Epstein-Barr virus (EBV) viremia

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: WGS

PreviouslyPublished: NR

Variant: HOMOZYGOUS 3061G>A (E1021K)

ClinVarID: 88675

CAID: N/A

gnomAD: not found in v2.1.1

SupplementalData: unknown

Note: Full access to article denied. Info in annotation gathered from abstract. Also, please be advised the curator translated the article from Chinese to English, and mistranslations are possible.

PMID: 29673649

Gene: PIK3CD

HGNC: 8977

Case#: case_Kiyota_2018, female,1 yo (onset), Japanese ancestry reported

DiseaseAssertion: APDS + 22q13 deletion syndrome

FamilyInfo: de novo

CasePresentingHPOs: (HP:0001973, HP:0000969, HP:0011134, HP:0000123, HP:0000093, HP:0003073, HP:0004431, HP:0003493, HP:0020151, HP:0033604, HP:0001263, HP:0001290, HP:0000729, HP:0002463, HP:0001249, HP:0007021, HP:0012433

ITP systemic edema mild fever lupus nephritis proteinuria hypoalbuminemia decreased complement levels antinuclear antibody double strand DNA antibody wire-loop lesions in glomeruli delayed psychmotor development hypotonia autistic features language delay intellectual disability reduced sensitivity to pain poor social functioning

CaseHPOFreeText: positive staining for IgG, IgA, IgM, C3 and C1q and electron-dense deposits observed through renal biopsy, along with wire-loop lesions

CaseNotHPOs: (HP:0030882, 0010783, HP:0030880) coronary aneurysm butterfly erythema Raynaud's phenomenon

CaseNotHPOFreeText: dysmorphic features

CasePreviousTesting: G-band karyotyping + whole genome SNP microarray revealed 22q13 deletion syndrome

GenotypingMethod: WES

PreviouslyPublished:

Variant: NM_005026.3:c.1534C > T; p.(Arg512Trp)

ClinVarID: 1347382

CAID: CA577258

gnomAD: v2.1.1 Grpmax 0.00007392 (4/18252 alleles) East Asian population

SupplementalData:

PMID: 29800648

Gene: PIK3CD

HGNC: 8977

Case#: 1_Edwards_2019, F, 40 yo (report), white ethnicity reported

DiseaseAssertion: APDS

FamilyInfo: NR

CasePresentingHPOs: EBV + (HP:0430064)

CaseHPOFreeText: NR

CaseNotHPOs: CMV, Lymphoma

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: NR

PreviouslyPublished: Yes PMID: 28414062

Variant: PIK3CD c.371G>A, p.G124D

ClinVarID: 2733822

CAID: CA338300460

gnomAD: not found

SupplementalData:

Case#: 3_Edwards_2019, F, 60 yo (report), white ethnicity reported

DiseaseAssertion: APDS

FamilyInfo: NR

CasePresentingHPOs: EBV +, diffuse large B-cell lymphoma (HP:0430064, HP:0002665)

CaseHPOFreeText: NR

CaseNotHPOs: CMV, Lymphoma (HP:0430087)

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: NR

PreviouslyPublished: No

Variant: PIK3CD c.1573G>A p.E525K

ClinVarID: 132807

CAID: n/a

gnomAD: not found

SupplementalData:

Case#: 2_Edwards_2019, F, 12 yo (report), African American ethnicity reported

DiseaseAssertion: APDS

FamilyInfo: NR

CasePresentingHPOs: EBV + (HP:0430064)

CaseHPOFreeText: NR

CaseNotHPOs: CMV, Lymphoma (HP:0430087, HP:0002665)

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: NR

PreviouslyPublished: Yes PMID: 24165795

Variant: PIK3CD c.1002C>A, p.N334K

ClinVarID: 132806

CAID: CA156204

gnomAD: not found

SupplementalData:

Case#: 12, M, 5 y.o., Ethnicity: Indian.

CasePresentingHPOs: HP:0001945 (Fever), HP:0001824 (Weight loss), HP:0002716 (Lymphadenopathy/FHL), HP:0003212 (Increased circulating IgE level), HP:0002716 (Lymphadenopathy), HP:0009098 (Chronic oral candidiasis), HP:0002841 (Recurrent fungal infections), HP:0032326 (Methicillin-resistant Staphylococcus aureus infection), HP:0020271 (Increased lymph-node eosinophils), HP:0100827 (Lymphocytosis), HP:0003237 (Increased circulating IgG level), HP:0002090 (Pneumonia)

CaseHPOFreeText: Eosinophils 17%, fungal scrapes—positive. Methicillin-resistant Staphylococcus aureus pneumonia, oral candidiasis/Hyper IgE.

Suspected recurring pneumonia.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Sanger sequencing and NGS targeting a customized panel of genes.

Variant: NM_005026.5:c.2296G>A.

ClinVar: 846790.

CAID: CA577485.

gnomAD: 0.00001611. https://gnomad.broadinstitute.org/variant/1-9722305-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: 11, M, Age of onset: <1 year. Ethnicity: Indian.

CasePresentingHPOs: HP:0002028 (Chronic diarrhea), HP:0004432 (Agammaglobulinemia), ORPHA:1572 (Common variable immunodeficiency), HP:0040218 (Reduced natural killer cell count), HP:0004315 (Decreased circulating IgG concentration), HP:0002720 (Decreased circulating IgA concentration), HP:0002850 (Decreased circulating total IgM)

CaseHPOFreeText: Proband has normal ferritin levels. Proband has abnormally low B cells (66), low IgG, IgA, IgM levels. Proband has abnormally low natural killer (NK) cell count.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Sanger sequencing and NGS targeting a customized panel of genes.

Variant: NM_005026.5:c.1394C>T.

ClinVar: 709503.

CAID: CA577186.

gnomAD: Frequency: 0.0004085. Link: https://gnomad.broadinstitute.org/variant/1-9720166-C-T?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: 13, M, Age of Onset: 2 y.o., Ethnicity: Indian.

CasePresentingHPOs: HP:0001954 (Recurrent fever), HP:0001876 (Pancytopenia)

CaseHPOFreeText: Proband has ALPS. Proband was reported to have borderline value for double negative TCRαβ+ T cells. Proband has normal range of B cells (484). Proband has normal IgG, IgA, IgM levels. Proband has normal range of NK cells.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Sanger sequencing and NGS targeting a customized panel of genes.

Variant: Variant 1: NM_005026.5:c.1726G>A. Variant 2: NM_005026.5:c.1394C>T.

ClinVar: Variant 1: 764550. Variant 2: 709503.

CAID: Variant 1: CA577314. Variant 2: CA577186.

gnomAD: Variant 1: Frequency: 0.00006758. Link: https://gnomad.broadinstitute.org/variant/1-9721163-G-A?dataset=gnomad_r4. Variant 2: Frequency: 0.0004085. Link: https://gnomad.broadinstitute.org/variant/1-9720166-C-T?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

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Case#: P01, Female, clinical diagnosis at the age of 45, genetic diagnosis at the age of 56, German, alive at the time of article's publication

DiseaseAssertion: Patient is classified as "Mildly affected" based on a CHAI score of 10.42%.

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.109+1G>T

ClinVar ID: 161113

gnomAD: This variant was not found in any gnomAD version.

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P23, Female, German, 46 years old at the time of clinical diagnosis, 46.2 years old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 15.56%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: ENST00000302823.7:c.511A>C

ClinVar ID:

CAID: CA350138977

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P24, Female, 20 years old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: Unaffected based on a CHAI score of 6.67%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.515C>T (p.Ser172Leu)

ClinVar ID: 546887

gnomAD: 0.00001549 https://gnomad.broadinstitute.org/variant/2-203871435-C-T?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P25, male, German, 16 years old at the time of clinical diagnosis, 40.8 years old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 43.75%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: ENST00000302823.7:c.536T>G

ClinVar ID:

CAID: CA350139037

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P26, male, German, 9 years old at the time of clinical diagnosis, alive at the time of publication

DiseaseAssertion: Mildly affected based on a CHAI score of 10.42%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.619A>G (p.Thr207Ala)

ClinVar ID: 1307969

gnomAD: 0.00001177 https://gnomad.broadinstitute.org/variant/2-203872759-A-G?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P02, Female, the age of clinical and genetic diagnosis: Unknown, Finnish, alive at the time of article's publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NC_000002.12:g.203868053T>A

ClinVar ID:

CAID: CA350138070

gnomAD: not found in any gnomAD version.

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P03, Male, Age: N/A, ethnicity: N/A, Alive at the time of article's publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.155G>A (p.Gly52Asp)

ClinVar ID: 871301

gnomAD: not found in any gnomAD version.

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P04, male, genetic diagnosis at the age of 71.4, ethnicity: N/A, Dead at the time of article's publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.160G>A (p.Ala54Thr)

ClinVar ID: 430905

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P05, Male, age: n/a, ethnicity:n/a, alive at the time of publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: <br /> NM_005214.5(CTLA4):c.208C>T (p.Arg70Trp)

ClinVar ID: 161114

gnomAD: 6.195e-7 https://gnomad.broadinstitute.org/variant/2-203870684-C-T?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P06. Female, German, 52 years old at the time of clinical diagnosis, Alive at the time of publication

DiseaseAssertion: classified as "Severely affected" based on a CHAI score of 47.37%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.214A>C (p.Thr72Pro)

ClinVar ID: 546886

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P07, Male, German, 18 years old at the time of clinical diagnosis and 24.2 years old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: Mildly affected based on a CHAI score of 17.65%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: <br /> NM_005214.5(CTLA4):c.224G>A (p.Arg75Gln)

ClinVar ID: 943305

gnomAD: 0.000008673

https://gnomad.broadinstitute.org/variant/2-203870700-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P08, Female, Canadian, age: n/a, alive at the time of publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.257C>T (p.Ala86Val)

ClinVar ID: 661941

gnomAD: 0.00001859

https://gnomad.broadinstitute.org/variant/2-203870733-C-T?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P09, Male, age: n/a, ethnicity: n/a, alive at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.265T>C (p.Tyr89His)

ClinVar ID: 1391402

gnomAD: 0.000003717 https://gnomad.broadinstitute.org/variant/2-203870741-T-C?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P10, Female, German, 24 years old at the time of clinical diagnosis, 25 years old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 33.33%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.326G>A (p.Gly109Glu)

ClinVar ID: 542071

gnomAD: 0.0002354 https://gnomad.broadinstitute.org/variant/2-203870802-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P11, Female, German, age: n/a, alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 18.75%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.326G>A (p.Gly109Glu)

ClinVar ID: 542071

gnomAD: 0.0002354 https://gnomad.broadinstitute.org/variant/2-203870802-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P12, sex: n/a, age: n/a, ethnicity: n/a

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.326G>A (p.Gly109Glu)

ClinVar ID: 542071

gnomAD: 0.0002354 https://gnomad.broadinstitute.org/variant/2-203870802-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P13, Male, German, 38 years old at the time of clinical diagnosis, 40.6 yeras old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: severly affected based on a CHAI score of 52.38%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: ENST00000295854.10:c.356T>G

ClinVar ID: not found

CAID:CA350138616

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P14, Female, Czech, 36 years old at the time of genetic diagnosis, daed at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: unregistered variant - without the bp change we can't confidently assert this variant at this time but it is possible it is CA2953901753

ClinVar ID: n/a

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P15, female, age: n/a, ethnicity: n/a, alive at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.384C>G (p.Ile128Met)

ClinVar ID: 662956

gnomAD: 0.000006814

https://gnomad.broadinstitute.org/variant/2-203870860-C-G?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P16, male, german, age: n/a, alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 45.83%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.392T>C (p.Val131Ala)

ClinVar ID: 624171

gnomAD: Not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P17, Male, Belgian, 40 years at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.407C>T (p.Pro136Leu)

ClinVar ID: 1711524

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P18, Female, German, 32.2 years old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: Mildly affected based on a CHAI score of 11.11%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.416A>G (p.Tyr139Cys)

ClinVar ID: 623475

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P22, Female, German, age: n/a , alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 42.86%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: ENSP00000497102.1:p.Leu163Ser

ClinVar ID:

CAID: PA2850594025

gnomAD: Not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P21, female, American, age: n/a, alive at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.467C>T (p.Pro156Leu)

ClinVar ID: 1035066

gnomAD: 0.00002292 https://gnomad.broadinstitute.org/variant/2-203871387-C-T?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P19, Female, Italian, age: n/a, alive at the time of diagnosis

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: ENST00000295854.10:c.434A>G

ClinVar ID:

CAID: CA350138791

gnomAD: 6.197e-7 https://gnomad.broadinstitute.org/variant/2-203870910-A-G?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P20, male, German, 22 years old at the time of clinical diagnosis, 22.7 years old at the time of genetic diagnosis, dead at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 42.11%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NP_001032720.1:p.Thr147Arg

ClinVar ID:

CAID: PA2850594024

gnomAD: Not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

General, Gene:CTLA4, HGNC:2505, PMID:31330498

PMID: 39253077

Gene: PIK3CD

HGNC: 8977

Case#: P1, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000490 (Deeply set eye/Ocular depression), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000540 (Hypermetropia/Hyperopia), HP:0000483 (Astigmatism), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001256 (Intellectual disability, mild/Mild impairment),

CaseHPOFreeText: Proband was noted to have readily visible veins and delayed bone age.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1615_1617del (p.Ile539del).

ClinVar: 60761.

CAID: CA344796.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P2, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000490 (Deeply set eye/Ocular depression), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001256 (Intellectual disability, mild/Mild impairment),

CaseHPOFreeText: Proband was noted to have readily visible veins and delayed bone age.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A..

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1465G>A (p.Glu489Lys).

ClinVar: 60762.

CAID: CA344798.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P3, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0001382 (Joint hypermobility/Hyperextensibility of joints), HP:0000490 (Deeply set eye/Ocular depression), HP:0000558 (Rieger anomaly), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000540 (Hypermetropia/Hyperopia), HP:0000483 (Astigmatism), HP:0000565 (Esotropia), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0000138 (Ovarian cyst), HP:0001256 (Intellectual disability, mild/Mild impairment), HP:0003100 (Slender long bone/Gracile long bones)

CaseHPOFreeText: Proband was noted to have delayed bone age and mild impairment and/or speech delay

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A..

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P4, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0000490 (Deeply set eye/Ocular depression), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000540 (Hypermetropia/Hyperopia), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin),

CaseHPOFreeText: Proband was noted to readily visible veins, normal mental development.

Proband was not evaluated for insulin resistance, ovarian cysts, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have hyperextensibility of joints, inguinal hernia, Rieger anomaly, astigmatism, myopia, esotropia, diabetes, frequent illnesses, mild impairment and/or speech delay.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P5, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0001382 (Joint hypermobility/Hyperextensibility of joints), HP:0000490 (Deeply set eye/Ocular depression), HP:0000558 (Rieger anomaly), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000545 (Myopia), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia),

CaseHPOFreeText: Proband was noted to have insulin resistance, frequent illnesses, ovarian cysts, normal mental development,

Proband was not evaluated for delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, hyperopia, astigmatism, esotropia, thin, wrinkled skin, readily visible veins, mild impairment and/or speech delay.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P6, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000490 (Deeply set eye/Ocular depression), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), (Micrognathia),

CaseHPOFreeText: Proband was not evaluated for inguinal hernia, Rieger anomaly, teeth delay, hyperopia, astigmatism, myopia, esotropia, lack of subcutaneous fat, insulin resistance, diabetes, thin, wrinkled skin, readily visible veins, frequent illnesses, ovarian cysts, normal mental development, mild impairment and/or speech delay, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have hyperextensibility of joints,

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P7, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000483 (Astigmatism), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0000347 (Micrognathia),

CaseHPOFreeText: : Proband was noted to have insulin resistance, ovarian cysts, normal mental development,

Proband was not evaluated for hyperextensibility of joints, ocular depression, hyperopia, myopia, esotropia, Triangular face, Mild midface hypoplasia, frequent illnesses, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, Rieger anomaly, thin, wrinkled skin, readily visible veins, mild impairment and/or speech delay,

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P8, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia),

CaseHPOFreeText: Proband was noted to have insulin resistance, thin, wrinkled skin, readily visible veins, frequent illnesses, normal mental development,

Proband was not evaluated for hyperextensibility of joints, teeth delay, hyperopia, astigmatism, myopia, esotropia, ovarian cysts, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, Rieger anomaly, mild impairment and/or speech delay.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1943dup (p.Arg649ProfsTer5).

ClinVar: 60764.

CAID: CA344800.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P9, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0004325 (Decreased body weight), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0000347 (Micrognathia),

CaseHPOFreeText: Proband was noted to have insulin resistance, normal mental development, mild impairment and/or speech delay,

Proband was not evaluated for height/length, occipitofrontal circumference, hyperextensibility of joints, teeth delay, hyperopia, astigmatism, myopia, esotropia, thin, wrinkled skin, readily visible veins, frequent illnesses, ovarian cysts, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, ocular depression, Rieger anomaly, Prominent forehead, Mild midface hypoplasia,

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1892G>A (p.Arg631Gln).

ClinVar: 126459.

CAID: CA347796.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: 14-year old female index patient, F, Age of Report:, Ethnicity: Austrian.

CasePresentingHPOs: HP:0001252 (Hypotonia), HP:0001945 (Fever), HP:0025297 (Prolonged), HP:0001873 (Thrombocytopenia), HP:0002155 (Hypertriglyceridemia), HP:0025435 (Increased circulating lactate dehydrogenase concentration/increased lactate dehydrogenase), HP:0003281 (Increased circulating ferritin concentration/markedly elevated ferritin), HP:0012156 (Hemophagocytosis),

CaseHPOFreeText: Here we investigated a 14-year old female index patient, born to non-consanguineous healthy Austrian parents, who was hospitalized with severe hypotonia and prolonged fever. She had neither lymphadenopathy nor hepatosplenomegaly, and no infectious agent was found. Initial laboratory findings showed a mild thrombocytopenia, hypertriglyceridemia, increased lactate dehydrogenase (LDH) and markedly elevated ferritin (Table 1 and Figure 1A), prompting work up for hemophagocytic lymphohistiocytosis (HLH). Hemophagocytosis was indeed visible in the bone marrow aspirate (Figure 1B). Soluble CD25 was mildly elevated at 2204 U mL-1 (Table 1) but below the levels typically seen in HLH.6 NK-cell activity as measured by CD107a expression upon stimulation was in the low normal range in the initial diagnostic (Table 1). The presence of fever, hypertriglyceridemia, hyperferritinemia and hemophagocytosis, did not allow the diagnosis of HLH, but gave evidence of macrophage activation in the context of a hyperferritinemic inflammatory syndrome (Table 1).6We initiated treatment with dexamethasone, leading to clinical improvement and normalization of LDH and ferritin levels. Tapering of dexamethasone resulted in clinical deterioration and rise in ferritin (Figure 1A), and was accompanied by the development of autoimmune neutropenia as documented by HNA-1b antibodies. As the disease was distinct from classical HLH,6 we decided to treat the patient with recombinant human anti-IL-1β (Anakinra, 100 mg twice daily) in combination with dexamethasone, rather than using the etoposide-based HLH-94 protocol. We discontinued dexamethasone treatment after eight weeks and, one month later, reduced the Anakinra dose to a maintenance dose of 100 mg daily. The patient has remained clinically stable and is currently receiving Anakinra (decreased to 60 mg once daily) without any inflammatory manifestations. Immunological characterization of patient peripheral blood in the asymptomatic phase after ceasing dexamethasone revealed reduced absolute natural killer (NK)-cell counts and low frequency of monocytes, and slightly low absolute lymphocyte counts (Table 1)..

CaseNotHPOs: N/A.

CaseNotHPOFreeText: She had neither lymphadenopathy nor hepatosplenomegaly, and no infectious agent was found.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: Variant 1: NM_001282426.2:c.145C>A (p.Arg49Ser) . Variant 2: NM_001282426.2:c.3254A>G (p.Asn1085Ser).

ClinVar: Variant 1: 1675220. Variant 2: 1675219.

CAID: Variant 1: CA4429087. Variant 2: CA368817268.

gnomAD: Variant 1: Frequency: 0.001519. Link: https://gnomad.broadinstitute.org/variant/chr7-106867706-C-A?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: A.1, F, Age of Report: 9 y.o., Ethnicity: European-American.

CasePresentingHPOs: HP:0012378 (Fatigue), HP:0001878 (Hemolytic anemia), HP:0006510 (Chronic pulmonary obstruction/early obstructive pulmonary impairment), HP:0003651 (Foam cells), HP:0004313 (Decreased circulating antibody concentration/Hypogammaglobulinemia), HP:0001873 (Thrombocytopenia), HP:0001888 (Lymphopenia), HP:0001880 (Eosinophilia), HP:0100721 (Mediastinal lymphadenopathy), HP:0034388 (Hilar lymph node enlargement), HP:0001744 (Splenomegaly), HP:0004387 (Enterocolitis), HP:0002014 (Diarrhea), HP:0002027 (Abdominal pain), HP:0002583 (Colitis), HP:0005425 (Recurrent sinopulmonary infections), HP:0410018 (Recurrent ear infections), HP:0001581 (Recurrent skin infections), HP:0000010 (Recurrent urinary tract infections), HP:0001742 (Nasal congestion), HP:0011010 (Chronic), HP:0000964 (Eczematoid dermatitis/Eczema),

CaseHPOFreeText: A female patient (hereafter called A.1) from a European-American family presented at nine years of age with fatigue and hemolytic anemia followed by early obstructive pulmonary impairment. A subsequent chest CT scan revealed bilateral nodular infiltrates and areas of patchy, peripheral-basal consolidation in lungs, and histological examination revealed a pattern of interstitial CD3+ lymphocytic infiltration, foamy histiocytes, scattered noncaseating granulomas, and luminal obstruction initially characterized as cryptogenic organizing pneumonia (Fig. 1a–b). Further follow up and analysis revealed clinical progression to hypogammaglobulinemia, thrombocytopenia, various lymphopenias, eosinophilia, mediastinal and hilar lymphadenopathy, and splenomegaly (Table 1). More recently, at sixteen years of age, patient A.1 developed enterocolitis with diarrhea and abdominal pain. Histological assessment of gut tissue revealed interstitial infiltrate of more than 25 CD3+ lymphocytes per 100 epithelial cells (Fig. 1b, bottom). Episodes of pneumonitis and colitis continue to recur intermittently, have an apparent noninfectious etiology (with separate incidences of infectious colitis), and respond to pulse doses of corticosteroids and steroid-sparing measures including mycophenolate mofetil.

The childhood of patient A.1 was remarkable for recurrent sinopulmonary, ear, skin, and urinary tract infections (commonly with S. aureus), chronic nasal congestion, and eczema. Additional episodes of colitis were sometimes associated with stool cultures positive for C. difficile and Salmonella. Vaccination responses were protective for tetanus, borderline protective for diphtheria, and protective for 4 of 23 pneumococcal strains. Warm autoimmune hemolytic anemia at nine years of age (preceding the initial pneumonitis by several months) was treated with steroids and blood transfusions; a recurrence of autoimmune cytopenias at seventeen years prompted CD20+ B cell depletion with rituximab. Patient A.1 is currently treated with immunoglobulin replacement therapy to restore humoral protection and mycophenolate mofetil to suppress inflammation.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES and Sanger.

Variant: NM_001282426.2:c.3062G>C (p.Arg1021Pro).

ClinVar: 1675218.

CAID: CA164129242.

gnomAD: Frequency: 0.00002988. Link: https://gnomad.broadinstitute.org/variant/chr7-106905140-G-C?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Patient A.1 inherited an allele from her healthy mother in whom a single base-pair deletion causes a frameshift beginning at R982 of p110γ, and an allele from her healthy father in whom a missense mutation results in an R1021P amino acid substitution in the kinase domain.

CasePMIDs: N/A.

PMID: 36826006

Gene: PIK3R1

HGNC: 8979

FamilyInfo: None relevant found

Disease: Sclerosing polycystic adenoma (SPA) fue to PIK3R1 haploinsuffiency , along with variant on HRAS and AR genes.

Prevalence: Estimated to be 1 in 200,000

CasePresentingHPOs: HP0000822 (hypertension), HP:6000862 (Parotid adenoma)

Case#: 15-year-old female, F, Age of Report: 15 y.o., Ethnicity: From China.

CasePresentingHPOs: HP:0001511 (Intrauterine growth retardation/Intrauterine growth restriction), HP:0004322 (Short stature), HP:0000684 (Delayed eruption of teeth/teething delay), HP:0000858 (Irregular menstruation/irregular menstrual cycle), HP:0001007 (Hirsutism), HP:0000820 (Abnormality of the thyroid gland/thyroid disease), HP:0005328 (Progeroid facial appearance/Progeroid facial appearance), HP:0000545 (Myopia), HP:0000678 (Dental crowding/overcrowded teeth), HP:0000855 (Insulin resistance)

CaseHPOFreeText: Proband was noted to have "characteristic facial gestalts/"characteristic facial dysmorphim", low weight at birth,

The proband was admitted to our department due to irregular menstrual cycle and hirsutism with short stature, who had a history of intrauterine growth restriction and presented with short stature, teething delay, characteristic facial gestalts, hirsutism, and thyroid disease. Whole-exome sequencing and Sanger sequencing revealed c.1960C > T, a novel de novo nonsense mutation, leading to the termination of protein translation (p. Gln654*).

This is the first case report of SHORT syndrome complicated with thyroid disease in China, identifying a novel de novo heterozygous nonsense mutation in PIK3R1 gene (p. Gln654*).

The phenotypes are mildly different from other cases previously described in the literature, in which our patient presents with lipoatrophy, facial feature, and first reported thyroid disease. Thyroid disease may be a new clinical symptom of patients with SHORT syndrome.

The patient was a girl born to a physically healthy and non-consanguineous couple by spontaneous delivery at the 37th week. Birth weight was 2150 g (− 3.39SD) and birth length was 44 cm (− 3.41SD), indicating that the patient had intrauterine growth restriction (IUGR). The proband also had teething delay, getting the first tooth at 1 year old. During childhood, the patient was bothered by short stature. Psychomotor and speech development was normal. The height of proband’s father and mother was 168 cm and 155 cm respectively. The patient also had a healthy 20-month-old brother.

At the age of 15 years and 4 months, the proband was referred to our department due to irregular menstrual cycle and hirsutism with a height of 149 cm (− 2.04SD), weight of 43 kg (− 1.22SD) and body mass index (BMI) of 19.4 kg/m2. The height of the proband had remained 149 cm, ever since 13 years old. Physical examination showed a triangular-shaped face, small chin, large low-set ears, thin lip, downturned mouth, obvious beard and bushy eyebrows (Fig. 1a,b,c,d). Oral examination showed overcrowded and irregular teeth, hypodontia, and severe dental caries (Fig. 1g). Pubertal development was assessed according to the Tanner stage, with pubic hair at PH5 stage and breast at B2 stage. The second phalanx of little finger in the left hand was short and thicken, which was confirmed with X-ray (Fig. 1e,f). Ultrasound of neck showed diffuse thyroid disease. Ultrasound biomicroscopy of the eyes, examination of ocular fundus, abdominal ultrasound, reproductive system ultrasound, and chest X-ray were normal. The cranial magnetic resonance imaging (MRI) indicated a small posterior pituitary.

Not evaluated on the proband: OFC at birth, thin, wrinkled skin with readily visible veins, inguinal hernia,

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have: Hyperextensibility of joints, ocular depression, Riegar anomaly, lipoatrophy, glaucoma, hyperopia, astigmatism, delayed bone age, intellectual deficiency, speech delay, diabetes, hearing loss, frequent infections, congenital heart diseases, pulmonary stenosis and ovarian cysts.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Whole-exome sequencing and Sanger sequencing.

Variant: NM_181523.3:c.1960C>T (p.Gln654Ter).

ClinVar: N/A.

CAID: CA359884699.

gnomAD: N/A.

VariantEvidence: A novel de novo heterozygous nonsense mutation in the PIK3R1 gene (p. Gln654*) was found in the proband.

WES was performed to make a clear clinical diagnose. The candidate variants were first screened by a minor allele frequency < 3% against the 1000 Genomes Project, the NHLBI exome variant server or in 50 HapMap control exomes. Then, short stature, facial abnormalities were selected as the filtering clinical symptoms to analyze the screened candidate variants. According to the guidelines recommended by the American College of Medical Genetics and Genomics, a pathogenic variant of PIK3R1 gene was identified to contribute to the patient’s conditions. Sequencing result indicated c.1960C > T of PIK3R1 gene a novel nonsense mutation, leading to the termination of protein translation (p. Gln654*), which was confirmed by sanger sequencing (Fig. 2). In addition, direct sequencing results showed the genotypes of proband’s parents were wild-type, suggesting it was a de novo mutation.

CaseAddInfo: The height of proband’s father and mother was 168 cm and 155 cm respectively. The patient also had a healthy 20-month-old brother.

CasePMIDs: N/A.

Case#: patient, M, Age of Report: newborn, Ethnicity: Korean.

CasePresentingHPOs: HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0003074 (Hyperglycemia), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000490 (Deeply set eye/Ocular depression), HP:0009125 (Lipodystrophy), HP:0000023 (Inguinal hernia), HP:0001642 (Pulmonic stenosis), HP:0001684 (Secundum atrial septal defect/ASD secundum), HP:0000684 (Delayed eruption of teeth)

CaseHPOFreeText: To the best of our knowledge, this is the first case report of SHORT syndrome with TNDM.

The patient was a newborn male and the only child of a healthy non-consanguineous Korean couple with a non-contributory family history. The height of his father and mother was 170 cm (−0.70 SD score) and 160 cm (−0.04 SD score), respectively. They had no dysmorphic features. The mother had regular antenatal check-up and did not have any history of medical and obstetric problems during pregnancy. He was born at 38 weeks of gestation but displayed features of IUGR during pregnancy. His birth weight was 1.8 kg (<3rd percentile), length 44 cm (<3rd percentile), and head circumference 31 cm (<3rd percentile) according to the Korean reference for birth weight based on gestational age and sex. The initial blood glucose level was 70 mg/dl. The baby was exclusively breastfed starting on day 3 and was in generally good condition. However, blood glucose level was between 218 and 263 mg/dl at 5 day of age. At the age of 20 day, his blood glucose level was still high (205–260 mg/dl), and the infant was referred to the endocrine clinic for persistent hyperglycemia assessment. On physical examination, several dysmorphic features (triangular-shaped face, prominent forehead, ocular depression, lipodystrophy at the lumbar region) and inguinal hernia were present. The systolic and diastolic blood pressure measurements were 74 and 42 mmHg, respectively. The serum c-peptide and insulin levels were 2.83 ng/ml (normal: 1.0–3.5) and 120 μU/ml (normal: 2.8–13.5), respectively. Baseline chemistry including serum blood urea nitrogen was 15.3 mg/dl (normal: 7.0–20.0), creatinine 0.9 mg/dl (normal: 0.6–1.2), aspartate aminotransferase 38 U/L (normal: 14–40), and alanine aminotransferase 16 U/L (normal: 9–45), as well as complete blood count profile were within normal range. Urinalysis showed no glucose or ketones. There was no sign of ketoacidosis and the patient had no type 1 diabetes autoantibodies (antibodies against glutamic acid decarboxylase, islet cell, islet antigen-2, and insulin). The liver and pancreas ultrasonography revealed no structural abnormality. Echocardiography at the age of 1 month confirmed mild pulmonary stenosis and ASD secundum (2 mm) which did not require surgical intervention. Neonatal diabetes mellitus (NDM) was suspected on the basis of hyperglycemia occurring within the first month of life that lasted for >2 weeks and required insulin therapy. At age of 25 day, clinical exome sequencing was performed to identify the genetic cause of NDM.

To monitor the glycemic level, his blood glucose was measured at the beginning of each feeding session. The patient was treated with subcutaneous insulin, and blood glucose level gradually stabilized. The blood glucose levels ranged from 110–250 mg/dl during the next 10 days. An adequate glucose level was achieved at 6 weeks of age without insulin treatment. His body weight was 4.4 kg (<3rd percentile) and his length was 61.6 cm (<3rd percentile) at 10 months of age. The patient experienced no hyperglycemic episode and the glycated hemoglobin was 5.0% and insulin level 2.8 μU/ml. At 10 months of age, the patient had no teeth erupted in the oral cavity.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Urinalysis showed no glucose or ketones. There was no sign of ketoacidosis and the patient had no type 1 diabetes autoantibodies (antibodies against glutamic acid decarboxylase, islet cell, islet antigen-2, and insulin). The liver and pancreas ultrasonography revealed no structural abnormality.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: TruSight One sequencing panel and Sanger sequencing.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: Segregation analysis could not be performed due to the unavailability of parental samples.

CasePMIDs: N/A.

Case#: proband, M, Age of Report: 8 y.o., Ethnicity: British.

CasePresentingHPOs: HP:0008846 (Severe intrauterine growth retardation), HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0001510 (Growth delay), HP:0011968 (Feeding difficulties/behavioral feeding difficulties), HP:0001263 (Global developmental delay/psychomotor development delay), HP:0000252 (Microcephaly), HP:0000684 (Delayed eruption of teeth/Dentition), HP:0100543 (Cognitive impairment/delayed intellectual development), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000582 (Upslanted palpebral fissure/upward-slanting palpebral fissures), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001187 (Hyperextensibility of the finger joints), HP:0010485 (Hyperextensibility at elbow), HP:0009125 (Lipodystrophy)

CaseHPOFreeText:The proband, 8 years of age, is the first child of non-consanguineous Caucasian parents. There are no manifestations of SHORT syndrome in the family. There is no family history of microcephaly or intellectual disability. Following an otherwise uneventful pregnancy, delivery was induced at 38 weeks of gestation on discovery of severe intrauterine growth restriction. His birth weight was 1.97 kg (<0.4th centile, −3.7 SD).

Despite adequate nutritional intake, the patient's growth was significantly delayed. At 12 months of age, his weight was 6.88 kg (<0.4th centile, −3.2 SD), length was 69.5 cm (1st centile, −2.98 SD) and head circumference was 39.5 cm (<0.4th centile, −5.26 SD). Enteral tube feeding was initiated at 9 months of age, which the patient continues to remain dependent on today. Despite extensive investigation of the proband's feeding disorder, no organic cause was identified, and he was diagnosed with behavioral feeding difficulties. Follow-up consultations revealed a persistent development delay and sustained striking microcephaly. Dentition did not start until the age of 2.5 years. At 6 years of age, his weight was 16.2 kg (1st centile, −2.39SD), length was 105.4 cm (1st centile, −2.47 SD) and head circumference was 43.8 cm (<0.4th centile, −6.16 SD). Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

Intellectual and psychomotor development is moderate to severely delayed. The patient first walked at 20 months, first smiled at 3 months and spoke his first words aged 3 years. At his current age of 8 years, he attends a special needs school and requires substantial multidisciplinary support. Magnetic resonance imaging of the brain and electroencephalogram performed at 12 months of age was normal. Neurometabolic investigation was also normal. Recurrent ophthalmology investigations revealed a myopic left eye and hypermetropic right eye at 4 years of age. No anterior chamber defects were noted and his ocular pressure was reported as normal. His hearing was formally assessed and reported as normal.

Facial dysmorphic features are subtle but present (see Figure 2): triangular face, prominent forehead, broad eyebrows, slight upward-slanting palpebral fissures, and hypoplastic alae nasi leading to an impression of low columnella nasi. The patient has thin, wrinkled skin with visible veins, most prominently seen on his chest wall. He has hyperextensibility in his finger and elbow joints. Of note, local lipodystrophy of his proximal finger phalanges is also observed.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

No anterior chamber defects were noted and his ocular pressure was reported as normal.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Chromosome breakage studies, Angelman methylation studies and a 60 gene developmental delay and epilepsy panel were normal. Comparative genomic hybridization microarray identified a likely benign maternally inherited Xp11.4 duplication (GRch X:38646145-38687854). Trio-exome sequencing revealed a de novo heterozygous missense variant, c.1456G>A (p.Ala486Thr) in PIK3R1 (NM_181523.3).

Variant: NM_181523.3:c.1456G>A (p.Ala486Thr).

ClinVar: N/A.

CAID: CA359881414.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo:N/A.

CasePMIDs: N/A.

Case#: 17-year-old female, F, Age of Report:17 y.o., Ethnicity: Cuban descent.

CasePresentingHPOs: HP:0001510 (Growth delay), HP:0004322 (Short stature), HP:0000696 (Delayed eruption of permanent teeth/secondary tooth eruption delay), HP:0000858 (Irregular menstruation/irregular menses), HP:0100607 (Dysmenorrhea), HP:0012384 (Rhinitis), HP:0002099 (Asthma), HP:0001025 (Urticaria), HP:0031796 (Recurrent), HP:0000403 (Recurrent otitis media), HP:0010606 (Hordeolum/hordeolums), HP:0031796 (Recurrent), HP:0012204 (Recurrent vulvovaginal candidiasis/vaginal candidiasis), HP:0032168 (Clostridium difficile colitis), HP:0004315 (Decreased circulating IgG concentration/low IgG levels), HP:0045082 (Decreased body mass index/low BMI), HP:0001382 (Joint hypermobility/hyperextensible joints), HP:0011220 (Prominent forehead), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0009765 (Low hanging columella), HP:0000219 (Thin upper lip vermilion/thin upper lip), HP:0007495 (Prematurely aged appearance/aged appearance), HP:0010976 (B lymphocytopenia/low absolute B cells), HP:0410376 (Increased proportion of naive CD8 T cells/elevated CD8 T cell),

CaseHPOFreeText: This is a 17-year-old female of Cuban descent, born to nonconsanguineous parents at 36 weeks gestational age to an uncomplicated pregnancy. Her birth weight and length were average for gestational age (7 pounds, 18 in.). She presented with a history of growth delay, short stature, and secondary tooth eruption delay. She measured below her growth curve at 1 year of age. She had growth hormone testing which resulted normal; however, she received growth hormone therapy from 3 to 10 years of age with a good response. At that time, she underwent genetic testing for short stature; however, no genetic causes of short stature were found. She has a history of irregular menses and dysmenorrhea with work-up for possible etiologies, including polycystic ovarian syndrome (PCOS), resulting negative. She has met all developmental milestones appropriately and has normal cognition.

She has nonallergic rhinitis, mild intermittent asthma, and acute recurrent urticaria. Her history of infections includes recurrent episodes of otitis media since she was toddler requiring placement of 3 sets of ear tubes and tonsillectomy and adenoidectomy. She has a history of recurrent hordeolums and frequent episodes of vaginal candidiasis attributed to the many courses of antibiotics she has received for her various infections. She had one episode of Clostridium difficile colitis 6 months prior to presentation to our clinic. Prior immunologic evaluation at a different institution at 9 years of age was remarkable for low IgG levels, which ranged from 435 to 511 mg/dL [ref 759–1549 mg/dL]. A skin prick test to aeroallergens resulted negative. She did not receive intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin therapy at that time.

Her physical exam was relevant for short stature (1 percentile, z = − 2.33), low weight for age (< 1 percentile, z = − 2.69), low BMI (15 percentile), and hyperextensible joints. Her facial features were significant for a prominent forehead, triangular face, low-hanging columella, thin upper lip, and aged appearance. Given concern for immune deficiency, a complete immune evaluation was obtained. Her results revealed hypogammaglobulinemia (IgG of 610 mg/dL [ref 694–1618 mg/dL]), with IgM and IgA within the reference range. The lymphocyte subset panel revealed remarkably low absolute B cells (34 cells/μL [ref 130–800 cells/μL]) and percentage (1% [ref 9–30%]). CD4 T cells were within the reference range, and CD8 T cell counts (1091 cells/μL [ref 240–890 cells/μL]) and percentage (40% [ref 17–36%]) were elevated. She had low CD4:CD8 ratio (0.84 [ref 1.00–2.90]). Follow-up B cell panel corroborated the finding of low absolute B cells (70 cells/μL [ref 100–500 cells/μL]) and revealed increased transitional B cells (6.6% CD19 + CD27-CD21-IgM+ [ref 0.5–2.8%]) and naïve B cells (5.9% CD19 + CD27-CD21-CD38- [ref 0.3–2.3%]). ImmunoCAP IgE to aeroallergens was negative, and total IgE was 2 kU/L [ref < 114 kU/L]. Vaccine boosters to S. pneumoniae, H. influenzae, diphtheria, and tetanus were given. Subsequent titers revealed protective antibodies to S. pneumoniae, H. influenzae, and diphtheria and absent response to tetanus. Her lymphocyte mitogen proliferation showed normal lymphocyte responses to phytohaemagglutinin, concanavalin A, and pokeweed mitogen. Viral testing was not performed. At this time, the decision was made to start amoxicillin prophylaxis and monthly IVIG replacement therapy.

After initiating treatment with IVIG, our patient did not have new episodes of ear or sinus infections. IgG levels have remained within normal limits with monthly IVIG therapy. Given the finding of a PIK3R1 pathogenic variant and its known associations with SHORT syndrome, she was referred to ophthalmology and endocrinology. Of note, she started complaining of frequent headaches, not associated with administration of IVIG. Brain and cervical spine MRI revealed a Chiari I malformation for which she is being evaluated by neurosurgery.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: She did not have protective titers to tetanus, diphtheria, pneumococcus, or influenzae.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Invitae primary immunodeficiency 207-gene panel was obtained.

Variant: NM_181523.3:c.1425+1G>C (n.336+1G>C).

ClinVar: 156009.

CAID: CA170736.

gnomAD: N/A.

VariantEvidence: Results revealed a heterozygous “pathogenic variant” in PIK3R1 (c.1425 + 1G > C) with an autosomal dominant mode of inheritance in association with APDS2. This variant is a missense point mutation affecting a donor splice site in intron 11, resulting in exclusion of exon 11 (Fig. 1). Her parents are not carriers of this pathogenic variant, indicating this is a de novo mutation.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: Affected Individual 1, F, Age of Evaluation: 2 y.o., Ethnicity: Affected individuals and family members were recruited from Medical Genetics Clinics in North America, Israel, and the United Kingdom.

CasePresentingHPOs: HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0000325 (Triangular face/Triangular facies), HP:0000490 (Deeply set eye/Ocular depression), HP:0007495 (Prematurely aged appearance/Aged appearance), HP:0010781 (Skin dimple/dimple), HP:0000430 (Underdeveloped nasal alae/Hypoplastic ala nasi), HP:0000558 (Rieger anomaly),

CaseHPOFreeText: Proband had clinical features of SHORT syndrome.

Birth weight: 1.556 kg at 36 weeks

Height (percentile): 76.5 cm (<3rd)

Weight (percentile): 8 kg (<3rd)

Head circumference (percentile): 43 cm (<3rd)

Bone age: normal

Rieger anomaly: right optic-pit anomaly

Teething delays or other: Yes

Development and cognition: Normal

Lipodystophy: Yes

CaseNotHPOs:

Hyperextensibility: No

Hernias: No

Glaucoma: No

Other anterior-chamber anomalies: No

Insulin resistance or diabetes: No

Hearing loss: No

Radiological features: None reported

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Exome capture and high-throughput sequencing of samples for affected individual 1 and her two unaffected parents (trio design)

Variant: NM_181523.3:c.1906_1907insC (p.Asn636ThrfsTer18).

ClinVar: 75303.

CAID: CA264226.

gnomAD: N/A.

VariantEvidence: First, we analyzed the data from affected individual 1 and her unaffected parents. Two de novo nonsynonymous variants were detected in the affected individual, and they were found to be absent in both parents. The first, SNV c.3656C>G (p.Ser1219Cys) (RefSeq accession number NM_001164496.1) in WDR52, is predicted to be a polymorphism by MutationTaster (see Web Resources). The second, frameshift insertion c.1906_1907insC (p.Asn636Thrfs∗18) (RefSeq NM_181523.2) in exon 14 of PIK3R1, generates a stop codon in the region encoding amino acid residue 654 and is expected to produce premature truncation of p85α, the longest protein isoform encoded by PIK3R1. No genes with two obvious deleterious mutations—one inherited from each parent—were detected.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: Affected Individual 3, M, Age of Evaluation: 10.4 y.o., Ethnicity: Affected individuals and family members were recruited from Medical Genetics Clinics in North America, Israel, and the United Kingdom.

CasePresentingHPOs: HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0000325 (Triangular face/Triangular facies), HP:0000490 (Deeply set eye/Ocular depression), HP:0007495 (Prematurely aged appearance/Aged appearance), HP:0000430 (Underdeveloped nasal alae/Hypoplastic ala nasi), HP:0000558 (Rieger anomaly), HP:0000750 (Delayed speech and language development/speech delay),

CaseHPOFreeText: Proband had clinical features of SHORT syndrome.

Birth weight: 2.22 kg at 40 weeks

Height (percentile): 126 cm (3rd)

Weight (percentile): 21.8 kg (<3rd)

Head circumference (percentile): 51.5 cm (25th)

Bone age: delayed by 24 months

Hyperextensibility: yes; especially small joints

Rieger anomaly: right-sided; temporal; posterior; embryotoxin

Other anterior-chamber anomalies: atypical irises with hypoplastic appearance on transillumination; poorly dilating, constricting pupils

Teething delays or other: yes; fusion of central and lateral incisors

Lipodystophy: Yes

Radiological features: slender, narrow iliac wings; slender long bones; “drumstick” distal phalanges; narrow upper thorax

Other: vitiligo since age 7 years; poor response to growth hormone; behavioral problems

CaseNotHPOs: N/A.

CaseNotHPOFreeText:

Hernias: No

Dimple: No

Glaucoma: No

Insulin resistance or diabetes: No

Hearing Loss: No

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Each individual was assessed by a medical geneticist, ophthalmologist, and/or pediatrician. The clinical description of the affected individuals is presented in Table 1. DNA was extracted according to standard protocols. Paternity was confirmed by the genotyping of nine polymorphic simple-tandem-repeat markers.

PIK3R1 was investigated by Sanger sequencing in affected individuals 3–5.

Variant: NM_181523.3:c.1971T>G (p.Tyr657Ter).

ClinVar: 131987.

CAID: CA347729.

gnomAD: N/A.

VariantEvidence: Affected individual 3 was found to have a nonsense mutation (c.1971T>G [p.Tyr657∗]) absent in both parents.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: Affected Individual 4, M, Age of Evaluation: birth to 18 years, Ethnicity: Affected individuals and family members were recruited from Medical Genetics Clinics in North America, Israel, and the United Kingdom.

CasePresentingHPOs: *HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0000325 (Triangular face/Triangular facies), HP:0000490 (Deeply set eye/Ocular depression), HP:0007495 (Prematurely aged appearance/Aged appearance), HP:0000430 (Underdeveloped nasal alae/Hypoplastic ala nasi), HP:0000558 (Rieger anomaly), HP:0000750 (Delayed speech and language development/speech delay), *

CaseHPOFreeText: Proband had clinical features of SHORT syndrome.

Birth weight: 2.52 kg at 38 weeks

Height (percentile): 132.5 cm at 11 years (5th)

Weight (percentile): 23.5 kg at 11 years (<3rd);

Head circumference (percentile): 45.5 cm at 20 months (3rd)

Bone age: delayed

• Rieger anomaly: right-sided; temporal; posterior; embryotoxin

Other anterior-chamber anomalies: atypical irises with hypoplastic appearance on transillumination; poorly dilating, constricting pupils

Teething delays or other: yes; fusion of central and lateral incisors

Lipodystophy: Yes

Radiological features: slender, narrow iliac wings; slender long bones; “drumstick” distal phalanges; narrow upper thorax

Other: vitiligo since age 7 years; poor response to growth hormone; behavioral problems*

CaseNotHPOs: N/A.

CaseNotHPOFreeText:

*Hernias: No

Dimple: No

Glaucoma: No

Insulin resistance or diabetes: No

Hearing Loss: No*

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Each individual was assessed by a medical geneticist, ophthalmologist, and/or pediatrician. The clinical description of the affected individuals is presented in Table 1. DNA was extracted according to standard protocols. Paternity was confirmed by the genotyping of nine polymorphic simple-tandem-repeat markers.

PIK3R1 was investigated by Sanger sequencing in affected individuals 3–5.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 75301.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: Affected individual 4 was found to have a missense mutation (c.1945C>T [p.Arg649Trp]) absent in both parents and predicted to be damaging by PolyPhen.

CaseAddInfo: N/A.

CasePMIDs: N/A.

PMID: 40022676

Gene: PIK3R1

HGNC: 8979

FamilyInfo: None relevant found

Disease: Osteoarthritis, PIK3R1 was negatively correlated with activated NK cells, also it was one of the most diferential expressed genes.

CasePresentingHPOs: HP:0002758 (Osteoarthritis)

PMID: 25488983 Gene: PIK3R1 HGNC: 8979 FamilyInfo: Four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1 ExperimentalAssay: Funcional studies in mice as animal model CasePresentingHPOs: HP0012647(Abnormal inflammatory response), HP0002110 (Bronchiectasis), HP0002716 (HP:0002716), HP0001873 (Thrombocytopenia), HP0001369 (Arthritis) Case1: age 32, sex female, ethnicity Turkish Case2: age 43, sex female, ethnicity Caucasian Case3: age 17, sex male, ethnicity Caucacsian Case4: age 5, sex male, ethnicity Chinese

Table S1 lists two additional INSR variants identified in the proband during whole exome sequencing:

1. NM_000208.3:c.*104A>G – a 3′ UTR variant, homozygous, annotated as benign in ClinVar (rs1051690).
2. NM_000208.3:c.2666G>A (p.Arg889Gln) – a heterozygous missense variant, classified as a variant of uncertain significance in ClinVar (rs187282966).

Case#: Patient 3a

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Bronchiectasis, Chronic diarrhea, Adenopathy, Splenomegaly, Malignant disease, Neurodevelopmental delay, Growth retardation, Increased IgM, Decreased IgA/IgG, EBV chronic replication, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

ClinVar:

CAID:

gnomAD:

Case#: Patient 3b

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Chronic diarrhea, Adenopathy, Splenomegaly, Neurodevelopmental delay, Growth retardation, Increased IgM, Decreased IgA/IgG, EBV chronic replication, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

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Case#: Patient 4a

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Splenomegaly, Neurodevelopmental delay, Growth retardation, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 4b

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Bronchiectasis, Adenopathy, Malignant disease, Growth retardation, Increased IgM, Decreased IgA/IgG, EBV chronic replication, CMV chronic replication, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 5

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Neurodevelopmental delay, Growth retardation, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 6

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Bronchiectasis, Adenopathy, Splenomegaly, Neurodevelopmental delay, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 7

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Chronic diarrhea, Adenopathy, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 9

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Malignant disease, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 11

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Splenomegaly, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 12

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Chronic diarrhea, Adenopathy, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 13

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Malignant disease, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 14

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Malignant disease, Neurodevelopmental delay, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 15

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 16

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Chronic diarrhea, Adenopathy, Malignant disease, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 17

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Malignant disease, Neurodevelopmental delay, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 18

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Splenomegaly, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 20a

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Splenomegaly, Malignant disease, Growth retardation, Increased IgM, Decreased IgA/IgG, EBV chronic replication, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

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CAID:

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Case#: Patient 20b:

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Malignant disease, Increased IgM, Decreased IgA/IgG, EBV chronic replication, CMV chronic replication, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 21

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 22

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

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Case#: Patient 23a

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

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Case#: Patient 23b

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Chronic diarrhea, Adenopathy, Malignant disease, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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Case#: Patient 24

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Neurodevelopmental delay, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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gnomAD:

Case#: Patient 25

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

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CAID:

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Case#: Patient 26

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

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Case#: Patient 27a

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

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CAID:

gnomAD:

Case#: Patient 27b

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Malignant disease, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

ClinVar:

CAID:

gnomAD:

Case#: Patient 29

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

ClinVar:

CAID:

gnomAD:

Case#: Patient 30

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Splenomegaly, Neurodevelopmental delay, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

ClinVar:

CAID:

gnomAD:

Case#: Patient 31

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant:

HGVS:

ClinVar:

CAID:

gnomAD:

Case#: Patient 10

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Neurodevelopmental delay, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant: c.1425+2_+3delTG

HGVS:

ClinVar:

CAID:

gnomAD:

Case#: Patient 1

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant: c.1425+1G>T

HGVS:

ClinVar: 156008

CAID:

gnomAD: absent

Case#: Patient 2

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant: c.1425+1G>C

HGVS:

ClinVar:

CAID: 156009

gnomAD: absent

Case#: Patient 8

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Adenopathy, Growth retardation, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant: c.1425+2T>G

HGVS:

ClinVar:

CAID: 446498

gnomAD: absent

Case#: Patient 19

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Splenomegaly, Malignant disease, Neurodevelopmental delay, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia, Splenomegaly

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant: c.1300-1G>C

HGVS:

ClinVar: 446500

CAID:

gnomAD: absent

Case#: Patient 28

DiseaseAssertion: APDS2

CaseHPOFreeText: Upper respiratory infections, Pneumonia, Adenopathy, Malignant disease, Growth retardation, Increased IgM, Decreased IgA/IgG, Inverted ratio CD4/CD8, ENT lymphoid hyperplasia

CasePreviousTesting: Genomic DNA from patients presenting with genetically undefined primary antibody deficiency was screened for mutations at the splice sites of exon 11 (coding exon 10) of the PIK3R1 gene by using whole-exome sequencing or targeted Sanger sequencing.

Gene: PIK3R1

Variant: c.1425+2T>A

HGVS:

ClinVar: 446497

CAID:

gnomAD: absent