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#: 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#: 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#: 20-year-old Spanish man

DiseaseAssertion: Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation

FamilyInfo: Maternally inherited CTLA4 variant and paternally inherited CLEC7A variant. Patient's mother had been diagnosed with mild sarcoidosis, dysphagia with eosinophilic infiltrates of esophagus, low IgM, and decreased percentages of memory B cells.

CasePresentingHPOs: HP:0100651 (Type I diabetes mellitus) HP:0001045 (Vitiligo) HP:0001047 (Atopic dermatitis) HP:0002205 (Recurrent respiratory infections) HP:0001541 (Ascites) HP:0002014 (Diarrhea) HP:0410151 (Eosinophilic infiltration of the esophagus) HP:0410147 (Eosinophilic infiltration in the stomach mucosa) HP:0033351 (Candida esophagitis) HP:0100806 (Sepsis) HP:0032061 (Hypereosinophilia) HP:0032064 (Gastrointestinal eosinophilia)

CaseHPOFreeText: Type 1 diabetes was diagnosed at 15 months old. Patient has a history of severe enteritis. Investigations, which were undertaken due to hypereosinophilia and eosinophilic infiltration, revealed a clonal γδ T cell band, characterized as reactive, with subsequent exclusion of FIP1L1-FDGFRA and PDGFRB rearrangements, as well as any abnormal karyotype. Sepsis was due to Salmonella typhi and Clostridium difficile infection.

Article provides functional evidence of CLEC7A variant affecting phenotype of this patient. Their data suggest that partial loss of DECTIN-1 in a patient with CTLA-4h may enhance IDAIL penetrance and confer additional unique phenotypes, with persistent marked hypereosinophilia as the most remarkable uncommon clinical manifestation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole-genome sequencing was performed on the patient's whole blood sample. The variants were confirmed with Sanger sequencing. Presence of a somatic CTLA4 variant was ruled out with high-coverage WGS of sorted peripheral T cells.

GenotypingMethod: Whole-genome sequencing was performed on the patient's whole blood sample. The variants were confirmed with Sanger sequencing. Presence of a somatic CTLA4 variant was ruled out with high-coverage WGS of sorted peripheral T cells.

PreviouslyPublished: No

Variant: NM_005214.5:c.208C>T p.Arg70Trp

ClinVar: 161114

CAID: CA173999

gnomAD: 0.000001313 https://gnomad.broadinstitute.org/variant/2-203870684-C-T?dataset=gnomad_r4

Variant: NM_197947.3:c.547C>T p.Leu183Phe

ClinVar: 717363

CAID: CA6443934

gnomAD: 0.01719 https://gnomad.broadinstitute.org/variant/12-10123309-G-A?dataset=gnomad_r4

SupplementalData: Detailed clinical info and and immunological test results can be found in Supplementary Materials.f

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 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 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.