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.

[[AD_VCEP_Annotation_Protocol_Updated.pdf]]

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

DiseaseAssertion: activated PI3Kδ syndrome 1(APDS1)

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole-exome sequencing

GenotypingMethod: Whole-exome sequencing

PreviouslyPublished: No

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

ClinVar: 88675

CAID: CA577192

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

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

ClinVar: 422410

CAID: CA16617216

gnomAD: Variant is not present in gnomAD data

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

ClinVar: 582515

CAID: CA338303813

gnomAD: Variant is not present in gnomAD data

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

ClinVar: Not present in ClinVar

CAID: CA338303802

gnomAD: Variant is not present in gnomAD data

Case#: Angulo_2014_P9, M, 15 months (onset), Irish/Danish ancestry reported

DiseaseAssertion: APDS

FamilyInfo: mother genotype/phenotype positive

CasePresentingHPOs: Recurrent respiratory infection, HP:0002205 Recurrent ear infection, HP:0410018 Splenomegaly, HP:0001744 Increased serum IgM, HP:0003496 Decreased IgG, HP:0004315 Decreased IgA, HP:0002720 Decreased tetanus antibodies, HP:0410295 Low levels of anti-pneumococcal antibodies, HP:0012476 Low levels of anti-Haemophilus Influenzae type B antibodies, HP:0410303 Decreased circulating T cells, HP:0005403 Decreased circulating B cells, HP:0010976 Increased circulating transitional B cells, HP:0030381 Decreased circulating class switched memory B cells, HP:0030388 Bronchiectasis, HP:0002110 lymphadenopathy, HP:0002716

CaseHPOFreeText: n/a

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: WES and Sanger

PreviouslyPublished: not reported

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

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S2

Case#: Angulo_2014_P8, M, 6 months (onset), origin in Slovenia

DiseaseAssertion: APDS

FamilyInfo: de novo confirmed

CasePresentingHPOs: HP:0002783, HP:0410018, HP:0002716, HP:0002014, HP:0032247, HP:0031693, HP:0001433, HP:0000620, HP:0030877, HP:0002720, HP:0003496, HP:0410303, HP:0032218, HP:0010976, HP:0030374, HP:0030388, HP:0030381 (recurrent LRTI, recurrent ear infections, massive generalized lymphadenopathy, cryptosporidium parvum diarrhoea, CMV and EBV infections, hepatosplenomegaly, chronic dacriocystitis requiring surgical intervention, mixed obstructive/restrictive FEV1/FVC, decreased IgA, increased IgM, decreased haemophilus B antibodies, decreased CD4+ T cells, decreased B cells, decreased IgM memory B cells; CD19+ CD27+ IgD+, decreased Class-switched memory B cells; CD19+ CD27+ IgD–, as % of CD19+, increased transitional B cells; CD19+ CD38+ IgM+, as % of CD19+

CaseHPOFreeText: decreased CD25+ as % CD3+, mastocytoma, increased CD8+ T cells, CD4+ CD25– CD127– as % of CD4+ T cells, increased CD8+ CD25– CD127– as % of CD8 T cells, as % of CD19+)

CaseNotHPOs:

CaseNotHPOFreeText: malignancy, abnormal CD4+ CD25+ CD127- as % of CD4+ regulatory T cells

CasePreviousTesting: fibroblast and blood samples taken to evaluate somaticism. Findings indicate the mutation was germline.

GenotypingMethod: WES and Sanger, followed by genome for parental confirmation.

PreviouslyPublished: not reported

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

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S2

Note: could lacrimal gland obstruction be considered atopy for phenotype scoring?

Case#: Angulo_2014_P5, M, 12 months old (onset), origin in England

DiseaseAssertion: APDS

FamilyInfo: Pedigree in figure 1. Affected sister, son, and niece

CasePresentingHPOs: HP:0002783, HP:0410018, HP:0003496, HP:0005403, HP:0032218, HP:0005415, HP:0010976, HP:0020112, HP:0000365, HP:0002878, HP:0033537, HP:0011950, HP:0001744, HP:0025289, HP:0030387, HP:0030381, HP:0030877 (recurrent lower respiratory tract infection, recurrent ear infection, elevated IgM, decreased T cells, decreased CD4+ T cells, decreased CD8+ T cells, decreased B cells, Increased proportion of CD4+CD25+ regulatory T cells, hearing impairment, type 2 respiratory failure, mosaic attenuation, inflammatory bronchiolitis, splenomegaly, cervical lymphadenopathy, increased class switched memory B cells, increased transitional B cells, mixed obstructive/restrictive FEV1/FVC,

CaseHPOFreeText: increased CD25+ as a percentage of CD3+, increased CD3+CD56+ as % of CD3+, increased proportion of CD4+ CD25+ CD127– CD45RA- regulatory T cells, increased proportion of CD8+ CD25+ CD127– CD45RA+ regulatory T cells, increased CD4+ CD25- CD127– CD45RA- as % of CD4+ peripherally expanded T cells, increased CD8+ CD25- CD127– CD45RA+ as % of CD8+ peripherally expanded t cells, severe necrotising pneumonia, hypoperfused right lung, recurrent salivar gland abscesses, CD

CaseNotHPOs: HP:0410242, HP:0410240 (abnormal IgG, abnormal IgA)

CaseNotHPOFreeText: malignancy

CasePreviousTesting:

GenotypingMethod: WES and Sanger

PreviouslyPublished: not reported

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

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S2

Case#: Schwab_2018_Patient_129, 16 y.o. (onset) and 19 y.o. (death), male, origin in Germany

DiseaseAssertion: CTLA4 Haploinsufficiency

FamilyInfo: mother (patient 128) was heterozygous with same variant. This patient was recored as 'affected' but type-1 diabetes was the only phenotype reported.

CasePresentingHPOs: HP:0001973, HP:0001945, HP:0001744, HP:0001058, HP:0004313, HP:0004315, HP:0002720, HP:0031378, HP:0002240, HP:0002716, HP:0002093, HP:0000964, HP:0001047 (ITP, fever, splenomegaly, wound healing disorder, hypogammaglobulinemia, low IgG, Low IgA, lymphoproliferation, hepatomegaly, lymphadenopathy, respiratory involvement, eczema, atopic dermatitis)

CaseHPOFreeText: organ infiltration (brain and lung), GLILD, neurological involvement,

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: n/a

CasePreviousTesting: unknown

GenotypingMethod: unknown

PreviouslyPublished: n/a

Variant: NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)

ClinVarID: 161109

CAID: CA173992

gnomAD: not found

SupplementalData: extensive data in S1

Note: functionally tested using transendocytosis

Case#: AAA.II.1, subject 130. Male. Age of Onset: 23y.o. Age of evaluation: 46 y.o. Origin in Switzerland, Caucasian.

DiseaseAssertion: Gastrointestinal involvement

FamilyInfo: None found

CasePresentingHPOs: HP:0008207 (Addison's disease), HP:0004313 (Hypogammaglobulinemia), HP:0002720 (Low IgA), HP:0002014 (Diarrhea), HP:0002242 (Enteropathy), HP:0012410 (PRCA/Pure red cell aplasia)

CaseHPOFreeText: Lymphoproliferation, Cytopenia, Autoimmune cytopenia, Endocrinological involvement, Kidney involvement

Lymphocytic or granulomatous organ infiltration of the gut

Thirty-five percent of affected mutation carriers (27/78) were under antibiotic prophylaxis. In one affected mutation carrier (the patient) treatment with vedolizumab (blocking α4β7 integrin) improved colitis, and in the same individual PRCA responded well to cyclosporine A.

IgG levels: no values were available before IVIG or Rituximab

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: Yes, Navarini et al. PMID: 27908448

Variant: NM_005214.5:c.257C>T

ClinVarID: 661941

CAID: CA2067080

gnomAD: 2:204735456 C / T

SupplementalData: extensive data in S1

Note: Functionally tested using transendocytosis

Case#: Schwab_2018_CaseVV.II.1, male, 7 .o. (onset) 13 y.o. (report), origin in Saudi Arabia, reported Caucasian ethnicity

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: Same variant observed in the father. Consanguinity reported

CasePresentingHPOs: HP:0002086, HP:0005523, HP:0011024, HP:0004313, HP:0002720, HP:0001744, HP:0002240, HP:0011947, HP:0002090, HP:0002110, HP:0031035, HP:0002242 (respiratory involvement, lymphoproliferation, gastrointestinal involvement, hypogammaglobulinemia, low IgA, splenomegaly, hepatomegaly, upper and lower RTIs, pneumonia, bronchiectasis, chronic infection, enteropathy, cytopenia (ITP))

CaseHPOFreeText: low IgM, Lymphocytic or granulomatous organ infiltration (lung, liver, gut), GLILD

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: unknown

PreviouslyPublished: no

Variant: c.359_359delG; p.A121fs*23

ClinVarID: not found

CAID: CA2573320362

gnomAD: not found

SupplementalData: extensive phenotype data in figure S1

Case#: U.II.1, subject 50. Male. Age of Onset: 3.75 y.o. Age of evaluation: 9 y.o. Origin in Japan, Asian

DiseaseAssertion: Diagnosis with CVID (later with CTLA4 insufficiency)

FamilyInfo: Patient is oldest of three siblings. All three have been genotyped, but only this proband is affected. Variant inherited from the father, who is also unaffected (pedigree in Figure 1).

CasePresentingHPOs: HP:0001873, HP:0001973, HP:0004313, HP:0002720, HP:0004315, HP:0002719, HP:0005353

CaseHPOFreeText: Cytopenia, Autoimmune cytopenia, hypogammaglobulinemia, low IgG, low IgA, Clinically reactivated/apparent Infections, Herpes Infection, clinical EBV infection (possibly chronic?), ITP, positive Coombs test

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: Unpublished

Variant: NM_005214.5(CTLA4):c.494G>A (p.W165*)

ClinVarID: N/A

CAID: CA350138939

gnomAD: This variant is not found in gnomAD v2.1.1.

SupplementalData: Extensive data in S1, including some phenotypes that were tested for but found to be absent.

Note: Not functionally tested using transendocytosis.

Case#: Wang_2022_P13, M, 8 y.o. (diagnosis), origin in

DiseaseAssertion: APDS

FamilyInfo:

CasePresentingHPOs:<br /> decreased T cells (HP:0005403) decreased B cells (HP:0010976) decreased CD4/CD8 (HP:0033222) increased IgM (HP:0003496) decreased CD19 increased transitional B cells (HP:0030381) decreased naive b cells (HP:0030372) increased plasmablasts (HP:0032128) decreased CD4 (HP:0032218) decreased CD4 naive (HP:0410378) decresed CD8 naive (HP:0410377) EBV viremia (HP:0020072) lymphadenopathy (HP:0002716) enteropathy (HP:0002242) thrombocytopenia (HP:0001873)

CaseHPOFreeText: increased CD4 CM, increased CD4 EM, increased CD8, increased CD8, CM increased CD8 EM

CaseNotHPOs: abnormal wbc count (HP:0011893) abnormal IgA (HP:0410240) abnormal IgG (HP:0410242) abnormal NK cells (HP:0012176) abnormal memory B cells (HP:0030373)

CaseNotHPOFreeText: abnormal CD3, abnormal CD8 temra, abnormal DNT

CasePreviousTesting:

GenotypingMethod: unclear- possibly WES or NGS

PreviouslyPublished:

Variant: heterozygous NM_005026.5:c.3074A>G (p.E1025G)

ClinVarID: 422410

CAID: CA16617216

gnomAD: Not present in gnomAD

SupplementalData: Table S1

Case#: Grammatikos_2021_Case2, female, 10 months (onset) 25 y.o. (report), origin not reported

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: Mother and brother are also affected. Extensive family history of autoimmune phenotypes in Figure S1.

CasePresentingHPOs: HP:0002315, HP:000340, HP:0003394, HP:0004313, HP:0012115, HP:0001878, HP:0007565, HP:0001744, HP:0004315, HP:0006577, HP:0002090, HP:0002829, HP:0005263, HP:0006532, HP:0033542, HP:0032174, HP:0002110, HP:0011473 (headache, peripheral paresthesia, muscle cramps, hypogammaglobulinemia, autoimmune hepatitis, hemolytic anaemia, cafe au lait spots, splenomegaly, low IgG, macronodular cirrhosis, fungal pneumonia, arthralgia, antral gastritis, recurrent bacterial pneumonias, bronchial wall thickening, diffuse tree-in-bud infiltrates, bronchiectasis, focal total villous atrophy)

CaseHPOFreeText: Severe lesion in right cerebellar hemisphere and left superior frontal gyrus. Evan's syndrome, bronchial associated lymphoid hyperplasia, intestinal metaplasia, intraepithelial lymphocytes

CaseNotHPOs: HP:0001369, HP:0012538 (artritis, response to gluten)

CaseNotHPOFreeText: n/a

CasePreviousTesting: 2 benign polymorphisms found in perforin gene. Other genes tested: Fas, Fas ligand, Caspase 10, Caspase 8, NRAS. Heterozygous VUS found in LRBA gene.

GenotypingMethod: not specified. It says, "Following her mother’s diagnosis of CTLA4 haploinsufficiency, she was confirmed to have the same genetic mutation." Mother was tested using NGS + Sanger

PreviouslyPublished: not reported

Variant: NM_005214.4(CTLA4):c.81_82insT (p.Leu28fs) heterozygous

ClinVarID: 644629

CAID: CA645516071

gnomAD: not found

SupplementalData: Figure S1 shows extensive family history

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

Case#: Collen_2022_Patient_1, female, infancy (onset) 23 y.o. (report), Ethnicity reported: white

DiseaseAssertion: CTLA4 haploinsifficiency

FamilyInfo: Mutation inherited from father, who had melanoma and was asymptomatic for autoimmunity. Paternal first cousin had type-1 diabetes. Mother and brother had no autoimmune symptoms to report.

CasePresentingHPOs: HP:0002014, HP:0001510, HP:0002608, HP:0003261, HP:0033637, HP:0011473, HP:0002900, HP:0001903, HP:0001944, HP:0002246, HP:0001973, HP:0000872, HP:0008207, HP:0003765, HP:0004315, HP:0410240, HP:0030374 (diarrhea, low growth, celiac disease, elevated TTG IgA, endomyosial antibody, absence of duodenal villi, secondary hypokalemia, anemia, dehydration, scalloping of duodenal folds, cytopenias, hashimoto thyroiditis, Addison disease, psoriasis, low IgG, low IgA, low memory B cells)

CaseHPOFreeText: possible lichen sclerosis, negative titers to varicella-zoster virus and mumps despite vaccination. Patient showed switched memory B cells 1.4%, unswitched memory B cells 4.9%, and intraepithelial lymphocytes. Additional diagnosis's: Celiac disease, Hashimoto thyroiditis, Addison disease, CVID

CaseNotHPOs: HP:0002718 (recurrent bacterial infections)

CaseNotHPOFreeText: abnormal stool culture

CasePreviousTesting: none

GenotypingMethod: Whole exome sequencing (research based)

PreviouslyPublished: not reported

Variant: NM_005214.5:c.457+2T>C

ClinVarID: not found

CAID: CA350138849

gnomAD: not found

SupplementalData: n/a

Note: Functional information present. Immunophenotyping using flow cytometery revealed diminished expression of CTLA4 on CD4+/Foxp3+/CD45RA− memory regulatory T cells (Tregs) (Figure 3A).

Case#: 2/M. 10 y.o. (onset) and 13 y.o. (at assessment), male

DiseaseAssertion: Patient had thrombocytopenia, associated bleeding, neutropenia, and lymphoid hyperplasia in lungs, lymph nodes, and brain, refractory to immunomodulatory therapy. The diagnosis of CTLA4 haploinsufficiency was made retrospectively in 7 patients who underwent HSCT for life-threatening, treatment-resistant immune dysregulation and in 1 patient prospectively (unclear which patients were identified retrospectively and prospectively).

FamilyInfo: None provided

CasePresentingHPOs: HP:0001873 (Thrombocytopenia), HP:0001875 (Neutropenia), OMIM:188030 (Immune thrombocytopenic purpura/ITP), HP:0001904 (Autoimmune neutropenia)

CaseHPOFreeText: ITP and autoimmune neutropenia, Reactive lymphoid hyperplasia—lymph nodes, lung, frontal lobe brain.

All 8 patients received steroids and a calcineurin inhibitor before transplant

Five patients (including this patient) had peripheral blood HSC grafts and received cyclosporine and mycophenolate mofetil (MMF) for graft versus host disease (GvHD) prophylaxis.

Patient died 4 months post-transplant due to transplant-related mortality of severe acute gut GvHD (Acute grade IV gut).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Not found

GenotypingMethod: Not found

PreviouslyPublished: Yes, Schwab et al. PMID: 29729943

Variant: NM_005214.5:c.529T>G

ClinVarID: N/A

CAID: CA350139018

gnomAD: Not found

SupplementalData: More information regarding Lymphocyte subsets and Immunoglobulins in Table I. Table II contains variant information and Table III contains further details about HSCT and a breakdown of each patient's transplant procedure.

Note: No mention of whether or not the patient was tested using transendocytosis.

Case#:1/M. 1.5 y.o. (onset) and 14 y.o. (at assessment), male

DiseaseAssertion: Patient had arthritis, neutropenia and thrombocytopenia, lymphadenopathy, and abdominal pain. The diagnosis of CTLA4 haploinsufficiency was made retrospectively in 7 patients who underwent HSCT for life-threatening, treatment-resistant immune dysregulation and in 1 patient prospectively (unclear which patients were identified retrospectively and prospectively).

FamilyInfo: Father was noted to have Immune dysregulation, Cytopenias and Lymphoma. The patient's father was also noted to have a complex autoimmune disease and died after autologous HSCT for non-Hodgkin lymphoma.

CasePresentingHPOs: HP:0001369 (Arthritis), HP:0001875 (Neutropenia), HP:0001873 (Thrombocytopenia), HP:0002716 (Lymphadenopathy), HP:0002027 (Abdominal pain), HP:0002720 (Decreased circulating IgA level).

CaseHPOFreeText: Autoimmune pancytopenia, Recurrent abdominal pain, Arthritis

This patient was offered HSCT because of ongoing autoimmunity and risk of lymphoma because his father had complex autoimmune disease and died after autologous HSCT for non-Hodgkin lymphoma.

All 8 patients received steroids and a calcineurin inhibitor before transplant

Five patients (including this patient) had peripheral blood HSC grafts and received cyclosporine and mycophenolate mofetil (MMF) for graft versus host disease (GvHD) prophylaxis.

Patient had cytomegalovirus reactivation early post-HSCT and autoimmune hemolytic anemia 6 months post-HSCT, which responded to steroids; he is now off all medication.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Patient has low levels of IgA but IgG and IgM levels appear to be within normal range. See Table I.

CasePreviousTesting: Not found

GenotypingMethod: Not found

PreviouslyPublished: Yes, Schwab et al. PMID: 29729943

Variant: c.518G>A, p.G173E

ClinVarID: N/A

CAID: CA350138990

gnomAD: Not found

SupplementalData: More information regarding Lymphocyte subsets and Immunoglobulins in Table I. Table II contains variant information and Table III contains further details about HSCT and a breakdown of each patient's transplant procedure.

Note: No mention of whether or not the patient was tested using transendocytosis.

Case#: Buchbinder_2019_Patient 1, female, 11 y.o. (onset) 21 y.o. (report), Caucasian

DiseaseAssertion: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency

FamilyInfo: "maternal history of vitiligo, hypothyroidism, a maternal grandmother with hypothyroidism, and a maternal great grandmother with multiple sclerosis." mutation was present in the mother, maternal grandmother, and absent in the father.

CasePresentingHPOs: HP:0002113, HP:0001085, HP:0032070, HP:0000988, HP:0002027, HP:0002017, HP:0002014, HP:0001433, HP:0001973, HP:0004313, HP:0001888, HP:0001875, HP:0033608, HP:0002716, HP:0033583, HP:0002729, HP:0001945, HP:0032154, HP:0002829, HP:0032366, HP:0032296, HP:0005479, HP:0100633, HP:0004295, HP:0100279, HP:0032203, HP:0002633, HP:0030374, HP:0045080, HP:0005415, HP:0001882, HP:0002315, HP:0000505, HP:0001250, HP:0000225, HP:0001873

(nodular pulmonary infiltrates, papilledema, leptomeningeal enhancement, recurrent rashes, abdominal pain, vomiting, diarrhea, hepatosplenomegaly, immune cytopenias, hypogammaglobulinemia, lymphopenia, neutropenia, pulmonary nodules, adenopathy, lymphocytic pleocytosis, follicular bronchiolitis, follicular lymphoid hyperplasia, fevers, aphthous ulcerations, arthralgias, presence of direct antiglobulin, elevated IgG level, decreased IgE level, chronic esophagus inflammation, gastric mucosa inflammation, colon inflammation, intramucosal lymphoid nodules in colon, vasculitis, decreased memory B cells, decreased CD3+T, decreased CD8+T, decreased WBC, headache, decreased vision, seizures, gum bleeding, thrombocytopenia)

CaseHPOFreeText: autoantibodies were absent except for a positive direct antiglobulin test. Improvement with corticosteroids, faint oligoclonal bands documented yet absent on subsequent evaluation. brain lesions, elevated CD19+B, decreased NK,

CaseNotHPOs: abnormal bone marrow, abnormal bronchoscopy, abnormal IgA, abnormal IgM, positive anti neuronal antibody test

CaseNotHPOFreeText: n/a

CasePreviousTesting: none

GenotypingMethod: Sanger sequencing of CTLA4

PreviouslyPublished: not reported

Variant: heterozygous for NM_005214.5:c.151C>T

ClinVarID: 161109

CAID: CA173992

gnomAD: not found

SupplementalData: none

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.