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:

HGVS:

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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:

HGVS:

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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:

ClinVar:

CAID:

gnomAD:

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:

HGVS:

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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:

ClinVar:

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

PMID: 40971032

Gene: PIK3R1 HGNC: 8979

Gene: PIK3CD HGNC: 8977

Case#: Female, age of onset: 56, age at testing: 69, age of last documented clinical stability: 74

DiseaseAssertion: suspected hyperactivation of the PI3K pathway; implied earlier in the paper as "activated PI3Kδ syndrome (APDS)"

FamilyInfo: no relevant family history

CasePresentingHPOs: HP:0001878, HP:0012735, HP:0000975, HP:0002716, HP:0012387, HP:0001744, HP:6000143, HP:0004313, HP:0002721, HP:0006530, HP:0002788 (hemolytic anemia, cough, diaphoresis, lymphadenopathy, bronchitis, splenomegaly, perforated appendicitis, hypogammaglobulinemia, immunodeficiency, interstitial lung disease, recurrent upper respiratory tract infections)

CaseHPOFreeText: asthenia, sarcoidosis due to chronic granulomatous sarcoid-type inflammation without necrosis, bronchiectasis with bronchiolitis, wound infection, abdominal wall dehiscence, common variable immunodeficiency (CVID) with immune dysregulation, CVID-associated interstitial lung disease, granulomatous-lymphocytic interstitial lung disease

CaseNotHPOs: HP:0012759 (neurodevelopmental abnormalities)

CaseNotHPOFreeText: dysmorphic features, learning difficulties

CasePreviousTesting: clinical exome sequencing targeting genes associated with primary immunodeficiencies

GenotypingMethod: sequencing

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant: NM_181504.3(PIK3R1):c.5A > T (p.Tyr2Phe)

ClinVar: not found

CAID:CA3290217

gnomAD: 0.3004% https://gnomad.broadinstitute.org/variant/5-67586561-A-T?dataset=gnomad_r2_1

SupplementalData: There is no supplemental data, clinical timeline and schematic with noted variants are in Figure 2 and Figure 3

Case#: Female, age of onset: 13, age at testing: 32, age of last documented clinical stability: 34

DiseaseAssertion: suspected hypoactivation of the PI3K pathway

FamilyInfo: maternal grandmother with rheumatoid arthritis, eldest sister died at 4 months due to septic shock after enteritiis

CasePresentingHPOs: HP:0002028, HP:0001945, HP:0025085, HP:0100279, HP:0002090, HP:0012388, HP:0033256, HP:0004313 (recurrent diarrhea, fever, bloody diarrhea, ulcerative colitis (UC), pneumonia, and multiple episodes of acute bronchitis, pancolitis due to Clostridioides difficile infection, hypogammaglobulinemia)

CaseHPOFreeText: salmonellosis, psoriasis and psoriatic arthropathy affecting large joints, reduced B-cell compartment, bronchiectasis suggestive of CVID, unresponsive vaccination test, esophageal dysphagia, neutrophilic esophagitis

CaseNotHPOs: HP:0001249 (intellectual disability)

CaseNotHPOFreeText: dysmorphic features, patient has normal psychomotor and cognitive development,

CasePreviousTesting: clinical exome sequencing

GenotypingMethod: sequencing

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant: NM_005026.5(PIK3CD): [c.2608C > T (p.Arg870)] ; [c.2608C > T (p.Arg870)]

ClinVar: not

CAID:CA338307789

gnomAD: 0.0003%

SupplementalData: There is no supplemental data, clinical timeline and schematic with noted variants are in Figure 2 and Figure 3

CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review

PMID:40149457 Gene:CTLA4 HGNC:HGNC:2505

CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review

Case#: III:3, female, 45 years old, Italian

DiseaseAssertion: Celiac disease/IBD with immunodeficiency (CVID) and CNS demyelination

FamilyInfo: non-consanguineous Italian parents, history of autoimmune disorders (Hashimoto thyroiditis, psoriasiform dermatitis, celiac disease and rheumatoid arthritis), see Figure 1 CasePresentingHPOs: HP:0002028, HP:0002721, HPO:0001888, HPO:0008897, HP000:6515, HP:0002110, HP:0011108, HP:0001878, HP:0001973, HP:0031688, HP:0007185, HP:0002140, HP:0001081, HP:0011097, HP:0001945, HP:0007305, HP:0000238, HP:0200063, HP:0004313, HP:0000939, HP:0030252

CasePreviousTesting: whole-exome sequencing on the proband and parental DNA samples (trio-WES) from peripheral blood

GenotypingMethod: Reads aligned against GRCh38/hg38, variant calling using in-house pipeline according to international guidelines, variants with a frequency of <5% in gnomAD v4.1.0 and an in-house database, virtual panel of 564 genes related to primary immunodeficiency and inflammatory bowel disease (PanelApp version 7.21), CNVs detected with Control-FREEC and EXCAVATOR tools

**Variant: ** NM_005214.5:c.436G>A; p.Gly146Arg

ClinVar: VCV000849622.11

gnomAD: 0.000001696 https://gnomad.broadinstitute.org/variant/2-203870912-G-A?dataset=gnomad_r4

PMID: 40420664

GENE: PIK3R1

HGNC: 8979

Case#: 10-month‐old Japanese female

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: Her father has SHORT syndrome, with the same variant of PIK3R1, NM_181523.3:c.1957A>T, further described in Case 4. Her paternal grandmother "also manifests some facial characteristics of SHORT syndrome as well as a hearing impairment."

CasePresentingHPOs: HP:0001511, HP:0011220, HP:0000325, HP:0000430, HP:0004322, HP:0000490, HP:0000684, HP:0000331, HP:0000963, HP:0007392

CaseHPOFreeText: Born at 37 weeks of gestation with a birth length of 40.0 cm (−2.9 SD relative to the average for this gestational age) and birth weight of 1,676 g (−3.1 SD relative to the average for this gestational age) (Table 1). Her height and weight were 60.3 cm (−4.0 SD relative to the average for her age) and 4.01 kg (−7.6 SD relative to the average for her age), respectively, at the time of evaluation for the present study. Her fasting plasma glucose, serum IRI concentrations, and serum C‐peptide were 83 mg/dL, 2.6 μIU/mL, and 1.34 ng/mL, respectively, with an HbA1c level of 4.6%. Her HOMA‐IR was 0.53, and her HOMA‐β was 46.8%.

CaseNotHPOs: HP:0000819, HP:0000855, HP:0001382, HP:0000023, HP:0000558, HP:0000400, HP:0000369, HP:0000233, HP:0002714, HP:0005328, HP:0000540, HP:0000483, HP:0000545, HP:0000593, HP:0000501, HP:0100578, HP:0001249, HP:0000750, HP:0000365

CaseNotHPOFreeText: Readily visible veins

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1957A>T

ClinVar: 3767319

gnomAD: NR

SupplementalData: Table 1, Figure 1c,d

Case#: 20‐year‐old Japanese male

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: No relevant family history

CasePresentingHPOs: HP:0001511, HP:0000819, HP:0000855, HP:0040063, HP:0000484, HP:0000540, HP:0000483, HP:0000646, HP:0000684, HP:0000325, HP:0011220, HP:0000430, HP:0000331, HP:0000233, HP:0002714, HP:0100578

CaseHPOFreeText: Born at 39 weeks of gestation with a birth length of 45 cm and a birth weight of 1,990 g (−3.0 SD relative to the average for this gestational age). Weight at time of diagnosis was 38.5 kg (−1.2 SD), height 163.4 cm (−2.7 SD), body mass index 14.4 kg/m2 (−2.1 SD). He was found to have glycosuria during a school urine test at the age of 12 years and started treatment with metformin for diabetes at 15 years. Fasting plasma glucose, serum immunoreactive insulin (IRI) concentrations, and serum C‐peptide at evaluation were 161 mg/dL, 35.8 μIU/mL, and 5.20 ng/mL, respectively. HOMA‐IR was 14.2, and his HOMA‐β was 131.5%. Patient has facial characteristics of SHORT syndrome and adipose tissue atrophy in the upper body.

CaseNotHPOs: HP:0004322, HP:0001382, HP:0000023, HP:0000490, HP:0000558, HP:0000369, HP:0005328, HP:0000545, HP:0000593, HP:0000501, HP:0000963, HP:0007392, HP:0001249, HP:0000750, HP:0000365, HP:0000400

CaseNotHPOFreeText: Readily visible veins

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1945C>T

ClinVar: 60763

gnomAD: NR

SupplementalData: Table 1

Case#: 6‐year‐old Japanese female

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: No relevant family history

CasePresentingHPOs: HP:0001511, HP:0000855, HP:0004322, HP:0000490, HP:0000684, HP:0000325, HP:0000430, HP:0000400, HP:0000369, HP:0005328, HP:0000545, HP:0000963, HP:0007392, HP:0000365

CaseHPOFreeText: Born with a birth length of 43.1 cm (−1.3 SD relative to the average for this gestational age) and birth weight of 1,544 g (−2.7 SD relative to the average for this gestational age). Her height was 104.0 cm and weight 12.6 kg at the time of evaluation for this study, indicating no apparent short stature (−1.0 SD relative to the average for this age). Her fasting plasma glucose, serum IRI concentrations, and serum C‐peptide were 108 mg/dL, 56.4 μIU/mL, and 6.95 ng/mL, respectively, with an HbA1c level of 5.2%. Her HOMA‐IR was 15.0, and her HOMA‐β was 451.2%. She had a hearing threshold of 30 and 50 dB in the right and left ears, respectively. Otitis media was apparent in the right ear, but not in the left. Patient had readily visible veins.

CaseNotHPOs: HP:0000819, HP:0001382, HP:0000023, HP:0011220, HP:0000331, HP:0000233, HP:0002714, HP:0000540, HP:0000483, HP:0000593, HP:0000501, HP:0100578, HP:0001249, HP:0000750

CaseNotHPOFreeText: N/A

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1945C>T

ClinVar: 60763

gnomAD: NR

SupplementalData: Table 1, Figure 1a,b

Case#: 33-year‐old Japanese male

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: His daughter has SHORT syndrome, with the same variant of PIK3R1, NM_181523.3:c.1957A>T, further described in Case 3. His mother also manifests some facial characteristics of SHORT syndrome as well as a hearing impairment.

CasePresentingHPOs: HP:0008619, HP:0000365, HP:0000501, HP:0000819, HP:0001511, HP:0004322, HP:0000023, HP:0000490, HP:0000558, HP:0000325, HP:0011220, HP:0000430, HP:0000331, HP:0000400, HP:0005328, HP:0100578

CaseHPOFreeText: He was born at 36 weeks of gestation with a birth weight of 1,970 g. Weight at time of diagnosis was 44.2 kg (-2.4 SD), height 154 cm (-3.00SD) , body mass index 18.6 kg/m2 (-1.5 SD). He had been treated with a DPP‐IV (dipeptidyl peptidase‐IV) inhibitor and an SGLT2 inhibitor and manifesting an HbA1c level of 7.4% at the time of the current evaluation. His blood glucose and serum IRI levels at baseline and at 30, 60, 90, and 120 min after the glucose load were 130, 220, 238, 243, and 252 mg/dL and 8.0, 15.5, 25.6, 27.1, and 24.6 μIU/mL, respectively. His HOMA‐IR, HOMA‐β, and insulinogenic index were 2.57, 43.0%, and 0.083, respectively.

CaseNotHPOs: HP:0000855, HP:0001382, HP:0000684, HP:0000369, HP:0000233, HP:0002714, HP:0000540, HP:0000483, HP:0000545, HP:0000593, HP:0000963, HP:0007392, HP:0001249, HP:0000750

CaseNotHPOFreeText: Readily visible veins

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1957A>T

ClinVar: 3767319

gnomAD: NR

SupplementalData: Table 1, Figure 1e,f

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

Case#: P35

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (2 y), bronchiectasis, Chronic diarrhea, small intestinal nests, Lymphadenomegaly, splenomegaly, Inguinal hernia, nasosinusitis, mastoiditis, anti-infection prophylaxis, IVIG, glucocorticoid.

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#: P36

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (4 y), otitis media, Chronic diarrhea, gastritis, duodenal bulb inflammation, colitis, rectitis, Lymphadenomegaly, splenomegaly, hepatomegaly, Thrombocytopenia, IBD, Urinary tract infection, failure to thrive, nasosinusitis, mastoiditis, 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#: P37

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (3 y), otitis media, Lymphadenomegaly, splenomegaly, hepatomegaly, Osteomyelitis, contact dermatitis, 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#: P38

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Submaxillary lymph node enlargement, Otitis media, Lymphadenomegaly, splenomegaly, hepatomegaly, Nasosinusitis, failure to thrive, mastoiditis, anti-infection prophylaxis, 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#: P39

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (6 m), bronchiectasis (4.5 y), Lymphadenomegaly, splenomegaly, hepatomegaly, Osteomyelitis, nasosinusitis, thick corpus callosum, 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#: P40

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Purpura, Lymphadenomegaly, splenomegaly, hepatomegaly, Cutaneous vasculitis, 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#: P41

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Purpura, Recurrent respiratory tract infections (6 y), bronchiectasis (8 y), otitis media, Hematochezia, Lymphadenomegaly, splenomegaly, hepatomegaly, ITP, Failure to thrive, 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#: P42

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Abdominal pain, Recurrent respiratory tract infections (3 y), otitis media, Lymphadenomegaly, 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#: P1

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText:

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#: P2

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (1 m), pulmonary artery hypertension, bronchiectasis (16 y), Lymphadenomegaly, splenomegaly, hepatomegaly, Thrombocytopenia, Pericardial effusion, kidney injury, hypoalbuminemia, failure to thrive, 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#: P3

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (6 m), bronchiectasis (7 y), Lymphadenomegaly, splenomegaly, hepatomegaly, Pericardial effusion, warts, proteinuria, hypoalbuminemia, intracranial hypertension, convulsion, failure to thrive, nasosinusitis, mastoiditis, brain atrophy, 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#: P4

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Splenomegaly, Recurrent respiratory tract infections (9 y), Lymphadenomegaly, splenomegaly, SLE, lupus nephritis, AIHA, Flat warts, urinary tract infection, failure to thrive, 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#: P10

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Purpura, Recurrent respiratory tract infections, bronchiectasis (9 y), Chronic diarrhea, colitis, ileitis, gastritis, Lymphadenomegaly, splenomegaly, hepatomegaly, ITP, Mastoiditis, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1025G

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

ClinVar: 422410

CAID: CA16617216

gnomAD: absent from gnomad v4.1.0

Case#: P17

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (1.5 y), bronchiectasis (7 y), otitis media, hearing loss, Lymphadenomegaly, splenomegaly, hepatomegaly, ILD, Kidney stones, oblique inguinal hernia, failure to thrive, mastoiditis, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E525G

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

ClinVar: 582515

CAID: CA338303813

gnomAD: absent from gnomad v4.1.0

PMID: 40860302

Interesting SHORT syndrome article requiring annotation.

PMID: 39735640

Gene: PIK3R1

HGNC: 8979

Case#: 33-year-old Chinese adult female

DiseaseAssertion: Patient is asserted to have “SHORT syndrome due to a PIK3R1 gene variant (c.1945C > T).”

FamilyInfo: Both parents were healthy and non-consanguineous. Her father was 167 cm tall and her mother was 160 cm tall. The patient had a younger brother, aged 29, who was 175 cm tall and weighed 60 kg.

CasePresentingHPOs: HP:0000684, HP:0000750, HP:0040270, HP:0000855, HP:0004322, HP:0001382, HP:0000858, HP:0000558, HP:0011220, HP:0000430, HP:0000331, HP:0000233, HP:0000369, HP:0005328, HP:0007392, HP:0000963, HP:0100578, HP:0001952, HP:0000819, HP:0000147, HP:0000325

CaseHPOFreeText: Patient has a spontaneous full-term vaginal delivery without birth trauma or asphyxia. At birth, the patient weighed 2000 g (< 3rd percentile), though her length was unknown. Her first primary tooth emerged at 9 months and her ability to say “mom” and “dad” developed at 10 months. Throughout childhood, the patient consistently lagged in growth and development compared with their peers. At 5 years of age, her height was only 99.7 cm (−3 SD) and her weight 11.5 kg(< 3rd percentile). By age 9, her height was 116.5 cm (−3 SD) and her weight was 15.0 kg(< 3rd percentile). Her test results revealed a fasting blood glucose (FBG) level of 5.48 mmol/L and 2-hour postprandial blood glucose level of 8.04 mmol/L. Notably, her postprandial 2-hour insulin level exceeded the upper detection limit (> 2152.5 pmol/L), while her postprandial 2-hour C-peptide level was 0.4 nmol/L. Her glycosylated hemoglobin (HbA1c) was 5.78%. Consequently, she was prescribed long-term voglibose monotherapy. The patient exhibited distinctive facial features. The patient also exhibited visible veins and had polycystic ovarian syndrome. Height: 147.50 cm, Weight: 37.50 kg, BMI: 17.24 kg/m2, Lean mass: 23.90 kg, Fat mass: 9.30 kg, VFA: 35.3 cm2, Total cholesterol: 4.20 mmol/L, HDL-c: 1.09 mmol/L, LDL-c: 2.92 mmol/L, Triglyceride: 1.47 mmol/L, Calcium: 2.19 mmol/L, Phosphorous: 1.25 mmol/L, 25-hydroxyvitamin D3: 14.5 ng/ml, TSH: 1.97 mIU/L, Free T4: 11.47 pmol/L, Total testosterone: 1.47 nmol/L

CaseNotHPOs: HP:0001249, HP:0000956, HP:0002240, HP:0001397,<br /> HP:0000501, HP:0000488, HP:0009830

CaseNotHPOFreeText: Elevated plasma triglycerides, ocular hypotension, diabetic kidney disease, lower extremity arterial disease. The patient exhibited no lipid dysregulation, with fat mass and visceral fat area falling below the normal range, accompanied by a reduction in lean body mass.

CasePreviousTesting: NR

GenotypingMethod: Whole-exome sequencing

PreviouslyPublished: No

Variant: NM_181523.3:c.1945C>T

ClinVar: 60763

gnomAD: NR

SupplementalData: Table 1, 2, 3, 4

PMID: 41026257 GENE: PIK3CD HGNC: 8979

Case#: P3, 9-years-old Saudi girl

CasePresentingHPOs: HP:0002028, HP:0005425, HP:0100281

CaseHPOFreeText: P3 is a 9 years old girl with history of chronic diarrhea and recurrent sinopulmonary infections since the age of 4 months. Immunological evaluation at age of 3 years showed normal complete blood counts and differential, lymphocytes subsets, lymphocytes proliferation and oxidative burst assays. Her IgG level was 3.1 gm/L with normal IgA and IgM levels and her antibody response to pneumococcal polysaccharide vaccine could not be well assessed as she received conjugated pneumococcal vaccines (Table 1). Her recurrent chest infections improved after starting intravenous immunoglobulins. Upper and lower endoscopies showed architectural distortion with focal cryptitis from cecum, ascending and transverse colon biopsies and severe active chronic colitis with crypt abscesses and ulcerations from sigmoid and rectal biopsies with no viral cytopathic changes or granuloma. Her diarrhea was treated mainly with sulfasalazine therapy. Her weight and height are normal in spite of her chronic diarrhea.

Variant: NM_005026.4: c.433delinsGA: p.Q145Efs*51

GenotypingMethod: DNA from all individuals we had access to was submitted for whole-genome genotyping, to determine regions of autozygosity that are shared between all affecteds. This was done under the assumption of an autosomal recessive inheritance pattern, given the nature of the pedigree and the presence of parental consanguinity. Three such regions were highlighted by the software, of which the largest was a 12.3 Mb block on Chr 1 (Fig. 1B). Simultaneously we submitted the DNA from patient P1 for WES, and followed the NGS filtering scheme indicated in Fig. 1C. Once we had limited our search area to the regions of shared autozygosity which were exclusive to the three patients, no variants survived our filtering except for one

CAID: CA3252646241

**Case#: ** P1, 19-years-old Saudi male

**DiseaseAssertion: ** P1 is asserted to have "Crohn disease" and "CMV gastritis"

CasePresentingHPOs: HP:0002028, HP:0005425, HP:0000964, HP:0011473, HP:0200120

CaseHPOFreeText: P1 is a 19 year old boy with history of chronic diarrhea, recurrent sinopulmonary infections and dermatitis since the age of 2 months. At age of 1 year full upper and lower endoscopy showed duodenal villous atrophy and mild duodenitis, and antrum biopsy was suggestive of CMV gastritis with no significant colon biopsy findings. At 13 years of age he was evaluated by immunology service to rule out IEI. His complete blood counts and differential, lymphocytes subsets, lymphocytes proliferation and oxidative burst assays were normal. His IgG level was subnormal for age (4.2 gm/L) with undetectable IgM levels (Table 1). He was started on intravenous immunoglobulins with good clinical response in regard to his recurrent sinopulmonary infections. He continued to have chronic diarrhea that on frequent occasions was bloody, but he had normal weight gain and growth. Upper and lower endoscopies were performed on several occasions and showed severe chronic active colitis with ulcerations, epithelial reactive changes with granulomatous tissue formation suggestive of Crohn disease. His diarrhea responded partially to sulfasalazine therapy and short courses of steroids.

Variant: NM_005026.4: c.433delinsGA: p.Q145Efs*51

GenotypingMethod: DNA from all individuals we had access to was submitted for whole-genome genotyping, to determine regions of autozygosity that are shared between all affecteds. This was done under the assumption of an autosomal recessive inheritance pattern, given the nature of the pedigree and the presence of parental consanguinity. Three such regions were highlighted by the software, of which the largest was a 12.3 Mb block on Chr 1 (Fig. 1B). Simultaneously we submitted the DNA from patient P1 for WES, and followed the NGS filtering scheme indicated in Fig. 1C. Once we had limited our search area to the regions of shared autozygosity which were exclusive to the three patients, no variants survived our filtering except for one

CAID: CA3252646241

Case#: P2, 18-years-old Saudi girl

DiseaseAssertion: P1 is asserted to have "eosinophilic colitis"

CasePresentingHPOs: HP:0002028, HP:0005425, HP:0000964

CaseHPOFreeText: P2 is an 18 years old girl with history of chronic diarrhea, recurrent sinopulmonary infections and dermatitis since the age of 5 months. Immunological evaluation at age of 12 years showed normal complete blood counts and differential, lymphocytes subsets, lymphocytes proliferation and oxidative burst assays. Her IgG level was subnormal for age (3.6 gm/L) with undetectable IgM levels and poor antibody response to pneumococcal polysaccharide vaccine (Table 1). Her recurrent chest infections improved after starting intravenous immunoglobulins. She continued to have chronic diarrhea that was frequently bloody, but she also maintained normal weight gain and growth. Upper and lower endoscopies showed colonic heavy infiltration by eosinophils and focal eosinophilic abscesses consistent with eosinophilic colitis. Similar to her brother, the diarrhea responded partially to sulfasalazine therapy and short courses of steroids.

Variant: NM_005026.4: c.433delinsGA: p.Q145Efs*51

GenotypingMethod: DNA from all individuals we had access to was submitted for whole-genome genotyping, to determine regions of autozygosity that are shared between all affecteds. This was done under the assumption of an autosomal recessive inheritance pattern, given the nature of the pedigree and the presence of parental consanguinity. Three such regions were highlighted by the software, of which the largest was a 12.3 Mb block on Chr 1 (Fig. 1B). Simultaneously we submitted the DNA from patient P1 for WES, and followed the NGS filtering scheme indicated in Fig. 1C. Once we had limited our search area to the regions of shared autozygosity which were exclusive to the three patients, no variants survived our filtering except for one

CAID: CA3252646241

Case#: III.7, an 18-year-old female patient

DiseaseAssertion: immune thrombopenia, autoimmune hemolytic anemia, and Evans syndrome with infections early-onset herpes zoster and chronic Epstein-Barr virus

FamilyInfo: Table 1

CasePresentingHPOs: HP:0001433, HP:0002716

CaseHPOFreeText: severe necrotic dermohypodermitis of left leg caused by Pseudomonas aeruginosa, hypogammaglobulinemia

Variant: c.379T >G variant in CTLA4

GenotypingMethod: high-throughput sequencing

CAID: CA350138665

Case#: II.1, 61-years-old male (deceased)

DiseaseAssertion: Hashimoto disease

Variant: c.379T >G variant in CTLA4

CasePresentingHPOs: HP:0034954

CaseHPOFreeText: Anti-AChR antibodies without myasthenia gravis, unilateral uveitis, Staphylococcus aureus pneumoniae, Candida kefyr pneumoniae, Erythroderma, autoimmune alopecia, diffuse interstitial lung disease

Case#: II.4, 56-year-old male relative, age of onset 44

DiseaseAssertion: Spondylarthritis

Variant: c.379T >G variant in CTLA4

Case#: III.3, a diseased 31-year-old male relative, age of onset 7

DiseaseAssertion: Evans syndrome (ITP and AIHA)

CaseHPOFreeText: Lymphadenopathy, colic and renal nonclonal proliferation, Extensive chicken pox, viral encephalitis, EBV chronic viremia including inside tissues, Ear, nose and throat infections, pneumoniae, multiple Clostridium difficile colitis infections, Interstitial pneumopathy, Epilepsy, transverse myelitis C2 and T12, ADEM, Transplantation for interstitial fibrosis, late rejection with nonmalignant lymphoproliferation and EBV replication, Portal hypertension with diffuse nodular hyperplasia

Variant: c.379T >G variant in CTLA4

GenotypingMethod: high-throughput sequencing

CAID: CA350138665

Case#: III.4, a 34-year-old female relative, unknown age of onset

DiseaseAssertion: Hashimoto disease

Variant: c.379T >G variant in CTLA4

GenotypingMethod: high-throughput sequencing

CAID: CA350138665

Case#: IV.2, a 15 year old male realtive, unknown age of onset

CaseHPOFreeText: Ear, nose and throat infections; Dermatitis

Variant: c.379T >G variant in CTLA4

GenotypingMethod: high-throughput sequencing

CAID: CA350138665

Case# III.6, 27-year-old male relative, unknown age of onset

CaseHPOFreeText: Infectious mononucleosis, severe CMV infectious (nonautoimmune thrombocytopenia, splenomegaly, lymphadenopathy and hepatitis), Toxoplasma gondii infection, Dermatitis

Variant: c.379T >G variant in CTLA4

GenotypingMethod: high-throughput sequencing

CAID: CA350138665

Case#: II.3, a 59 year old female, age of onset 58

DiseaseAssertion: Inflammatory polyarthritis

FamilyInfo: Table 1

CaseHPOFreeText: presented with lymphoid proliferation, central nervous system inflammation (transverse myelitis and extensive disseminated encephalomyelitis), epilepsy, chronic kidney disease with one transplantation (benign polyclonal B-cell infiltration, interstitial fibrosis), interstitial pneumopathy, splenomegaly, hepatic abnormality with diffuse nodular hyperplasia, rectocolitis, extensive varicella zoster virus infection (VZV), viral encephalitis without documentation, Epstein–Barr virus (EBV) chronic viremia, Clostridium difficile severe colitis

Variant: c.379T >G variant in CTLA4

GenotypingMethod: high-throughput sequencing

CAID: CA350138665

Case#: 20-year-old male, Race: White (ancestry unavailable) DiseaseAssertion: The patient is asserted to have "CTLA4 haploinsufficiency" manifesting as aplastic anemia. FamilyInfo: Patient's father has disease variant Case PresentingHPOs: HP:0012378 (Fatigue), HP:0001962 (Palpitations), HP:0002875 (Exertional dyspnea), HP:0001903 (Anemia), HP:0001873 (Thrombocytopenia), HP:0002608 (Celiac disease), HP:0000608 (Macular degeneration), HP:0001876 (pancytopenia), HP:0001915 (aplastic anemia), CaseHPOFreeText: ** Diagnosis at age 20 when patient presented with persistent and profound incapacitating fatigue. Bone marrow biopsy was consistent to aplastic anemia. Table 1 summarizes presenting labs and flow cytometry results. Patient was first treated with high-dose IVIG, cyclosporine, and systemic corticosteroids. He initially responded well, but 6 months into therapy he developed renal impairment and was transitioned to sirolimus. His aplastic anemia relapsed. Patient underwent haploidentical (sibling, variant negative) hematopoietic stem cell transplantation, which was curative. CaseNotHPOs: HP:4000129 (Recent blood transfusion), CaseNotHPOFreeText: N/A CasePreviousTesting: The following studies were negative: Bone marrow chromosome analysis; FISH hybridization for BCR/ABL1, monosomy 5, monosomy 7, trisomy 8, and 20q deletion; myelodysplastic syndrome mutation sequencing. GenotypingMethod: A primary immunodeficiency NGS panel was run (gene content not specified) and identified a paternally inherited heterozygous missense variant in CTLA4. Variant: The patient is heterozygous for the NM_005214.5(CTLA4):c.385T>A (p.Cys129Ser). ClinVar: 1414930 CAID: N/A gnomAD**: This variant was not found in gnomAD v.4.1.0

PMID: 39220156 Gene: CTLA4 HGNC:2505

CTLA-4 functional assay performed to assess impact of NM_005214.5(CTLA4):c.385T>A (p.Cys129Ser) demonstrated impaired expression of CTLA-4. Figure 2 summarizes experimental results.

PMID: 41009791 Gene: CTLA4 HGNC: 2505

Case#: 15-year-old girl, ethnicity not specified DiseaseAssertion: The patient is asserted to have "CTLA-4 deficiency" FamilyInfo: CasePresentingHPOs: HP:0002315 (Headaches), HP:0002205 (Recurrent respiratory infections), HP:0007359 (Focal-onset seizure), HP:0001744 (Splenomegaly), HP:0002028 (Chronic diarrhea), HP:0005231 (Chronic gastritis), HP:0002875 (Exertional dyspnea), HP:0003139 (Panhypogammaglobulinemia) CaseHPOFreeText: Brain MRI showed multiple inflammatory lesions. CSF analysis showed elevated white cell count and protein levels. Figure 2 provides overview of clinical history and medical management. CaseNotHPOs: CaseNotHPOFreeText: Infectious diseases were excluded, including CMB, EBV, HIV, and mycobacteria. CasePreviousTesting: GenotypingMethod: Patient was tested via a targeted NGS panel. PreviouslyPublished: Not previously published. Variant: The patient harbors the NM_005214.5(CTLA4): c.394G>A (p.Glu132Lys) variant in the heterozygous state. ClinVar: 662200 gnomAD: This variant was not found in gnomAD v4.1.0 SupplementalData: Supplementary Table S1 contains full immunological workup.

PMID: 35945007

Gene: CTLA4

HGNC: 2505

Case#: 49-year-old woman

DiseaseAssertion: CTLA-4 deficiency-associated GLILD

FamilyInfo: Family history is negative for hereditary and immunological diseases

CasePresentingHPOs: HP:0031246, HP:0033709, HP:0002094

CaseHPOFreeText: Laboratory tests revealed decreased levels of serum globulin (IgG, IgA, and IgM) and pancytopenia. Serum soluble interleukin-2 receptor levels were elevated within the normal range for angiotensin-converting enzyme levels. Serum antibodies to human immunodeficiency virus (HIV) were within the normal CD4+ T-cell count limit at 1,079 /μL. A flow cytometric analysis demonstrated a decreased number of CD19+CD27+ memory B cells in the blood, with a selective decrease in IgG- and IgA-producing memory B cells. Chest radiography revealed bilateral infiltration of the lower lung fields while chest CT showed bilateral lower lobe reticular shadows as well as right middle lobe infiltrative and scattered nodular shadows in both the upper lobes. Bronchoalveolar lavage (BAL) showed increased cell counts (5.5×104/μL) and increased eosinophils, neutrophils, and lymphocytes in the cell fraction (eosinophils, 7%; neutrophils, 3%; lymphocytes, 25%; macrophages, 65%). The CD4/CD8 ratio in the lymphocytes was within the normal range (CD4/CD8 ratio: 1.06). A transbronchial lung biopsy revealed mild lymphocytic and eosinophilic infiltration of the cell septa. A pathological examination at low magnification revealed collapsed alveolar spaces with surrounding fibrotic changes, and at high magnification, thickened alveolar walls, nodule formation with lymphocyte and plasma cell infiltration, and lymphatic follicles were found. Polypoid plugs of loose organizing connective tissue (Masson bodies) within alveoli and small granulomas were also present. The infiltrated lymphocytes were CD3- or CD20-positive.

CaseNotHPOFreeText: Autoantibodies also tested negative. Bacterial and mycobacterial culture for chronic lower respiratory tract infections were negative. IgG4-positive cells were not detected. There was no neutrophil accumulation or presence of fungus, Gram-positive and/or Gram-negative bacteria, or acid-fast bacteria that would have suggested infection. No findings of vasculitis or malignant tumors were noted.

CasePreviousTesting: NR

GenotypingMethod: NR

PreviouslyPublished: NR

Variant: NM_005214.5:c.160G>A

ClinVar: 430905

CAID: CA350138187

gnomAD: NR

SupplementalData: Table, Fig 1a-c, Fig 2a-f

PMID: 31045771

Gene: PIK3CD

HGNC: 8977

Case#: 15-year-old Chinese boy

DiseaseAssertion: Patient was diagnosed with systemic lupus erythematosus (SLE) at a young age and was recently found to carry heterozygous mutations in PIK3CD. Diagnoses: Activated PI3Kδ syndrome

FamilyInfo: Family history revealed that his mother died of gastric cancer. Whole exome sequencing was performed in patient and in his father, when he was at the age of 15 and the PIK3CD gene was found to exhibit good coverage.

CasePresentingHPOs: HP:0002725, HP:0005425, HP:0032218, HP:0002716, HP:0000093, HP:0020072, HP:0000790, HP:0001882, HP:0001903, HP:0003493, HP:0025289, HP:0001744, HP:0004322, HP:0550004, HP:0001873, HP:0003565, HP:0011227, HP:0020026, HP:0032230, HP:0002110, HP:6001383, HP:0033726, HP:0033493, HP:0012574

CaseHPOFreeText: Serum level of complements was low, such as C3, C4, and CH50. Serum level of IgM and IgE was elevated, but IgG and IgA was normal. Lung CT scan showed partial consolidation of left upper lung with bronchiectasis and left upper bronchial stenosis. Renal biopsy was also done because of persistent hematuria and proteinuria, and it displayed moderately increased mesangial matrix and mesangial hypercellularity under the light microscope; subepithelial deposits was noted, and some mesangial changes may be present as seen in electron microscopy. Immunofluorescence was positive for C1q, C3, IgG, IgM, and Fb (Fig. 2). The patient was given oral prednisolone and hydroxychloroquine combined with mycophenolate mofetil. Six months later, the level of complement was restored to normal, hematuria and proteinuria disappeared, and liver function returned to normal. He was currently receiving intravenous immunoglobulin in association with hydroxychloroquine, low-dose prednisolone, and mycophenolate mofetil, with a good efficacy.

CasePreviousTesting: NR

GenotypingMethod: Whole exome sequencing, Sanger sequencing

PreviouslyPublished: No

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

ClinVar: 88675

gnomAD: chr1-9726972-G-A

SupplementalData: Figure 1, 2, 3

PMID: 41904601 GENE: CTLA4 HGNC: 2505

Case#: Patient 1 (P1) is a 24-year-old Chinese female.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patient's father carries the same CTLA4 variant as the patient but has been asymptomatic. No other family history reported.

CasePresentingHPOs: HP:0031245 (Productive cough), HP:0002105 (Hemoptysis), HP:0001878 (Hemolytic anemia), HP:0006532 (Recurrent pneumonia), HP:0004313 (Decreased circulating immunoglobulin concentration, HP:0033608 (Pulmonary nodule), HP:0002716 (Lymphadenopathy), HP:0001596 (Alpecia),

CaseHPOFreeText: Patient first presented at age 14 with respiratory symptoms. She was hospitalized at age 16 with hemolytic anemia and recurrent pulmonary infections. Lab work showed hypogammaglobinemia. Chest CT showed scattered solid and ground-glass density nodules bilaterally in the lungs, Lung biopsy demonstrated lymphocytic infiltration and siderophages. Treatment with corticosteroids achieved temporary remission, but the patient relapsed with dose tapering. She developed Evans syndrome, alopecia, and skin lesions. Disease stabilized with weekly subcutaneous abatacept (125mg) and the interval was subsequently extended to once every 4 weeks.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0032230 (Cytoplasmic antineutrophil antibody positivity).

GenotypingMethod: Genotyping was performed by whole exome sequencing.

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.4(CTLA4):c.155G>T(p.Gly52Val) variant.

ClinVar: 1420586

gnomAD: The variant was not found in gnomAD v4.1.1.

SupplementalData: No supplemental data provided.

Case#: Patient 2 (P2) is a 23-year-old Chinese male.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patient's father and oldest sister are both positive for the same CTLA4 variant. Both the parents and two older sisters are asymptomatic. The TNFRSF13B variants were not found in the parents or sisters.

CasePresentingHPOs: HP:0002254 (Intermittent diarrhea), HP:4000055 (Intestinal inflammation), HP:0002582 (Atrophic gastritis), HP:0004313 (Decreased circulating immunoglobulin concentration), HP:0030167 (Antimitochondrial antibody positivity)

CaseHPOFreeText: Patient presented at 12 years old with intermittent diarrhea, predominantly mushy stools with ocassional watery stools. Colonoscopy at age 21 demonstrated histopathological evidence of acute and chronic inflammation. Gastroscopy showed chronic atrophic gastritis and duodenitis. Treatment with intravenous immunoglobulin and biweekly subcutaneous abatacept (125 mg) led to clinical improvement.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0032230 (Antineutrophil antibody positivity)

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant1: The patient is heterozygous for the NM_005214.4 CTLA4):c.538C>T (p.Leu180Phe) variant.

CAID1: CA350139042

gnomAD1: This variant has a minor allele frequency of 0.0001370 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr2-203871458-C-T?dataset=gnomad_r4).

Variant2: The patient is heterozygous for the NM_012452.3(TNFRSF13B):c.83G>A variant.

ClinVar2: 1063279

gnomAD2: This variant has a minor allele frequency of 0.00009130 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr17-16952562-C-T?dataset=gnomad_r4)

Variant3: The patient is heterozygous for the NM_012452.3(TNFRSF13B):c.716C>T

ClinVar3: 471370

gnomAD3: This variant has a minor allele frequency of 0.0002962 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr17-16939713-G-A?dataset=gnomad_r4)

SupplementalData: There is no supplemental data.

Case#: Patient 3 (P3) is a 20-year-old Chinese female.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patient's brother died at age 15 from pancytopenia. The patient's mother was diagnosed with large granular lymphocytic leukemia. Patient's mother (Patient 4) also harbors the same CTLA4 variant as the patient. Authors do not indicate if patient's brother had genetic testing.

CasePresentingHPOs: HP:0001744 (Splenomegaly), HP:0001369 (Arthritis), HP:0020062 (Decreased hemoglobin concentration), HP:0011873 (Abnormal platelet count), HP:0002254 (Intermittent diarrhea), HP:0001876 (Pancytopenia), HP:0020026 (Positive Coombs test)

CaseHPOFreeText: Patients symptoms onset at 9 years old with chronic eczema, Evans syndrome, and splenomegaly. Initially responded well to corticosteroids and IV Ig, but relapsed after steroid tapering. She developed polyarthritis at age 16, diagnosed as juvenile idiopathic arthritis. She also developed photosensitive rashes. She was hospitalized due to pancytopenia and heavy vaginal bleeding. Anti-kertain antibody (AKA) and antiperinuclear factor were negative. Treatment with subcutaneous abatacept injections (125mg) resolved joint pain and brought hemoglobin and platelet counts to normal range.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0034092 (Anti-cyclic citrullinated peptide antibody positivity), HP:0002923 (Rheumatoid factor positive),

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.347T>A (p.Ile116Asn) variant.

ClinVar: 2430678

gnomAD: The variant was not found in gnomAD v4.1.1.

SupplementalData: There is no supplemental data.

Case#: Patient 4 (P4) is a 60-year-old Chinese woman.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: Patient's daughter is Patient 3 and harbors the same CTLA4 variant.

CasePresentingHPOs: HP:0001954 (Recurrent fever) HP:0011110 (Recurent tonsillitis), HP:0000155 (Oral ulcer), HP:0005558 (Chronic leukemia)

CaseHPOFreeText: Patient's symptoms onset in childhood with recurrent fever and tonsillitis. She experienced recurrent oral ulcers starting around age 50. She was diagnosed with large granular lymphocytic (LGL) leukemia for which she was treated with long-term corticosteroids for three years. She is currently treated with oral cyclosporine.

CaseNotHPOs: HP:0000988 (Skin rash)

CaseNotHPOFreeText: Patient denied history of rash, dry mouth, or dry eyes.

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.347T>A (p.Ile116Asn) variant.

ClinVar: 2430678

gnomAD: The variant was not found in gnomAD v4.1.1

SupplementalData: There is no supplemental data.

Case#: Patient 5 (P5) is a 19-year-old Chinese female.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patients mother, who harbors the same CTLA4 variant reported a history of chronic urticaria, alopecia areata, and intermittent diarrhea for over 10 years.

CasePresentingHPOs: HP:0001903 (Anemia), HP:0007418 (Alopecia totalis), HP:0002254 (Intermittent diarrhea), HP:0000964 (Eczematoid dermatitis), HP:0002716 (Lymphadenopathy), HP:0004818 (Paroxysmal nocturnal hemoglobinuria), HP:6000344 (Anti-intrinsic factor antibody positivity), HP:0000988 (Skin rash), HP:0004386 (Gastrointestinal inflammation), HP:0034839 (Lymphoid hyperplasia), HP:0040088 (Abnormal lymphocyte count), HP:0020062 Decreased hemoglobin concentration, HP:0025066 (Decreased mean corpuscular volume), HP:0025547 (Decreased mean corpuscular hemoglobin concentration)

CaseHPOFreeText: Patient's symptoms onset at age 10. Gastrointestinal endoscopy showed chronic inflammation and lymphoid hyperplasia. Patient has been treated with subcutaneous injections of abatacept (125mg) with notable clinical improvement. Fine white hair has started to regrow on her scalp, eyebrows, and eyelashes, and facial skin shows mild scaling.

CaseNotHPOs:

CaseNotHPOFreeText: Autoimmune screening including antinuclear antibodies were negative.

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.151C>T (p.Arg51Ter) variant.

ClinVar: 161109

gnomAD: The variant was not found in gnomAD v4.1.1.

SupplementalData: There is no supplemental data.

Case#: Patient 6 (P6) is an 18-year-old Chinese male.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: Patient denied family history of inborn error of immunodeficiency. The patient's father harbors the same CTLA4 variant as the patient. No symptoms are reported in the patient's father.

CasePresentingHPOs: HP:0001954 (Recurrent fever), HP:0012735 (Cough), HP:0002829 (Arthralgia), HP:0002113 (Pulmonary infiltrates), HP:0002716 (Lymphadenopathy), HP:0006532 (Recurrent pneumonia), HP:0004313 (Decreased circulating immunoglobulin concentration

CaseHPOFreeText: MRI of knees showed patchy abnormal signals in the right femoral and lateral condylar regions suggestive of bone marrow edema, with surrounding soft tissue edema. Mild joint effusion and suprapatellar bursa fluid were also noted. Treatment with avatacept was started and at the six-month follow-up the patient reported clinical improvement. He had no fever or sputum production and symptoms of lymphadenopathy and joint pain had improved.

CaseNotHPOs: HP:0001386 (Joint swelling), HP:0000988 (Skin rash), HP:0002014 (Diarrhea), HP:0003493 (Antinuclear antibody positivity), HP:0034092 (Anti-cyclic citrullinated peptide antibody positivity), HP:0002923 (Rheumatoid factor positive), HP:0032230 (Cytoplasmic antineutrophil antibody positivity)

CaseNotHPOFreeText:

CasePreviousTesting: None noted.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.436G>A(p.Gly146Arg) variant.

ClinVar: 849622

gnomAD: This variant has an allele frequency of 0.000001696 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr2-203870912-G-A?dataset=gnomad_r4)

SupplementalData: There is no supplemental data.

Case#: Patient 7 (P7) is a 50-year-old Chinese male.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo:

CasePresentingHPOs: HP:0012735 (Cough), HP:0002014 (Diarrhea), HP:0000988 (Skin rash), HP:0001596 (Alopecia), HP:0004313 (Decreased circulating immunoglobulin concentration), HP:0004386 (Gastrointestinal inflammation)

CaseHPOFreeText: Patient's symptoms onset in his late 30s with respiratory and gastrointestinal symptoms. He developed pruritic rashes on the abdomen and bottom of the feet, as well as alopecia. Gastrointestinal histopathology finding included intestinal metaplasia in the gastric angle and pyloric mucosa, as well as lymphoid follicle formation in the descending duodenum.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0034092 (Anti-cyclic citrullinated peptide antibody positivity),

CaseNotHPOFreeText: Patient was negative for inflammatory bowel disease antibodies.

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant1: The patient is heterozygous for the NM_005214.4 CTLA4):c.151C>T(p.Arg51Ter) variant.

ClinVar1: 161109

gnomAD1: The variant was not found in gnomAD v4.1.1.

Variant2: The patient is heterozygous for the NM_012452.3(TNFRSF13B):c.788C>T (p.Thr263Ile) variant.

ClinVar2: 1696714

gnomAD2: This variant has an allele frequency of 0.00009138 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr17-16939641-G-A?dataset=gnomad_r4)

Variant3: The patient is heterozygous for the NM_012452.3(TNFRSF13B):c.178C>T (p.Arg60Cys) variant.

CAID3: CA8414096

gnomAD3: This variant has an allele frequency of 0.00006666 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr17-16952467-G-A?dataset=gnomad_r4)

SupplementalData: There is no supplemental data.

PMID: 39689284 Gene: CTLA4 HGNC: 2505

Case#: The patient is a 39-year-old female with symptom onset at 14.

DiseaseAssertion: The patient is asserted to have "CTLA-4 happloinsufficiency." "Affected patients develop cytopenia, lymphoproliferative disorders, and hypogammaglobulinemia and are prone to a variety of autoimmune phenomena."

FamilyInfo: None provided

CasePresentingHPOs: HP:0001873 (Thrombocytopenia), HP:0001888 (Lymphopenia), HP:0001903 (Anemia), HP:0004313 (Decreased circulating immunoglobulin concentration), HP:0002028 (Chronic diarrhea), HP:0002024 (Malabsorption), HP:0001596 (Alopecia), HP:4000055 (Intestinal inflammation), HP:0006824 (Cranial nerve paralysis), HP:0002090 (Pneumonia), HP:0001269 (Hemiparesis)

CaseHPOFreeText: CSF analysis showed intrathecal synthesis of immunoglobulins G and M. MRI showed disseminated T2-hyperintense lesions, some lesions indicated long-lasting gadolinium enhancement (Figure 1A). PET scan-guided brain biopsy showed sustained myeline integrity, massive infiltration of T cells, and presence of few perivascular B cells. Infectious or neoplastic conditions were ruled out.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Laboratory testing was negative for infectious or rheumatologic conditions. Brain vessel angiography was normal.

CasePreviousTesting: None reported.

GenotypingMethod: Sequencing of the LRBA and CTLA4 genes was performed. Authors did not elaborate on methodology or assay.

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.5(CTLA4):c.322_323insT (p.Ser108MetfsTer46) variant.

CAID: CA3270658428

gnomAD: This variant is not found in gnomAD v4.1.1.

SupplementalData: Figure 1A shows MRI scans from 2014-2021. Figure 1B shows immunomodulatory treatment of the patient. Figure 1C shows blood lymphocyte count and lymphocyte subsets over time. Figure 1D shows Crohn disease activity index, blood platelet count, and serum immunoglobulins. Figure 2 shows single-cell RNA sequencing of peripheral blood monocular cells.

PMID: 41845460 Gene: PIK3CD HGNC: 8977

Case#: 3-year-old male

DiseaseAssertion: Activated phosphoinositide 3-kinase delta syndrome (APDS)

CasePresentingHPOs: HP:0034839, HP:0005425, HP:0020071, HP:0012189

CaseHPOFreeText: We describe a 3-year-old patient with a novel variant in the PIK3CD gene (c.58G > A p.(Val20lle)) presenting with EBV viremia, Hodgkin lymphoma, upregulation T follicular helper cells and CD10 + B cells consistent with a phenotype of APDS in a 3-year-old boy.

Variant: c.58G > A p.(Val20lle)

CAID: 1359338

PMID: 34097529

Gene: CTLA4

HGNC: 2505

Case#: A 51-year-old woman

FamilyInfo: the patient (and her affected family members) were heterozygous for a novel, likely pathogenic frameshift deletion variant in CLTA-4 exon

CasePresentingHPOs: HP:0002018, HP:0002141, HP:0003474, HP:0002110, HP:0001891, HP:0000964, HP:0001973, HP:0011108, HP:0100512

CaseHPOFreeText: necrotising granulomatous lymphadenitis, osteonecrosis of the jaw induced by bisphosphonates, diverticulitis, and bowel salt malabsorption. The patient’s daughter had recurrent episodes of CNS inflammation as a child and in adulthood she developed autoimmune hepatitis, autoimmune haemolytic anaemia and bronchiectasis.

FamilyInfo: The patient’s daughter had recurrent episodes of CNS inflammation as a child and in adulthood she developed autoimmune hepatitis, autoimmune haemolytic anaemia and bronchiectasis. The patient’s son was known to have type I diabetes, thyroid disease, pernicious anaemia and autoimmune encephalitis. FAS sequencing for autoimmune lymphoproliferative syndrome (ALPS) was normal and, at the time of presentation, extended panel screening for primary immunodeficiency was ongoing. There was prior exposure to corticosteroids but no other immunomodulatory treatment.

Variant: c.81dup p.(leu28Serfs*32)

ClinVar: 644629

GenotypingMethod: a virtual sub-panel of 194 genes associated with primary immunodeficiencies screened using Agilent ‘Focused Exome’ custom target enrichment system (SureSelectXT) and Next Generation Sequencing demonstrated that the patient (and her affected family members) were heterozygous for a novel, likely pathogenic frameshift deletion variant

PMID: 41608053 Gene: CTLA4 HGNC: 2505

Case#: Patient 16 (P16) is a female child, ethnicity not specified.

DiseaseAssertion: The patient is asserted to have CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI)

FamilyInfo: Sanger sequencing of other family members revealed the same CTLA4 variant in seven females across four generations, all of whom are symptomatic with autoimmunity and/or recurrent infections. See Figure 1A for pedigree.

CasePresentingHPOs: HP:0004880 (Respiratory infections in early life), HP:0003256 (Abnormality of te coagulation cascade), HP:0001954 (recurrent fever), HP:0000967 (Petechiae), HP:0002014 (Diarrea), HP:0003270 (Abdominal distention), HP:0025085 (Bloody diarrhea), HP:0001943 (Hypoglycemia), HP:0034315 (Chronic cough), HP:0000010 (Recurrent urinary tract infections), HP:0000076 (Vesicoureteral reflux)

CaseHPOFreeText: In infancy the patient was hospitalized multiple times for respiratory viral infections and an episode of transient coagulopathy. She continued to experience respiratory infections, prolonged bleeding with transient coagulopathy, and intermittent bloody diarrhea. Patient had intermittent elevated lactate. Flow cytometry demonstrated normal lymphocyte subsets and immunoglobulin concentrations were within normal limits. Soluble IL-2 receptor levels were elevated. Gastrostomy tube was placed at 26 months due to recurrent hypoglycemia and poor growth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole exome sequencing performed at 18 months old reported no diagnostic variants. Mitochondrial genome analysis was normal.

GenotypingMethod: Genotyping was performed via whole exome sequencing, which initially did not identify any diagnostic variants. Research analysis of the clinical exome data identified the CTLA4 variant.

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.5: c.654T>A (p.Tyr218*) variant.

ClinVar: 2440604

gnomAD: This variant has an allele frequency of 0.0006536 in gnomAD v4.1.1 (https://gnomad.broadinstitute.org/variant/chr3-38011318-G-A?dataset=gnomad_r4)

SupplementalData: N/A

PMID: 39624103 Gene: CTLA4 HGNC: 2505

Case#: The patient is male, 3 years and 10 months old. Ethnicity not specified

DiseaseAssertion: The patient is asserted to have CTLA-4 insufficiency.

FamilyInfo: Patient's mother has type 1 diabetes and autoimmune thyroiditis. The patient's maternal aunt has celiac disease and Lenox-Gastaut syndrome.

CasePresentingHPOs: HP:0001873 (Thombocytopenia), HP:0011947 (Respiratory tract infection), HP:0000988 (skin rash), HP:0000967 (Petechiae), HP:0034752 (Axillary lymphadenopathy), HP:0001047 (Atopic dermatitis), HP:0001903 (Anemia), HP:0012234 (Agranulocytosis),

CaseHPOFreeText: Patient had a mild upper respiratory tract infect followed by a small-spotted hemorrhagic rash and skin bruising. Physical examination was significant for punctate petechiae on skin and soft palate, as well as enlarged axillary lymph nodes bilaterally. On a subsequent visit patient was

CaseNotHPOs:

CaseNotHPOFreeText: Bone marrow biopsy did not reveal any abnormalities.

CasePreviousTesting:

GenotypingMethod:

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant:

ClinVar:

gnomAD:

SupplementalData: