Case#: Q.II.1, subject 44. Male. Age of Onset: 10 y.o. Age of evaluation/death: 15 y.o. Origin in UK, Caucasian.

DiseaseAssertion: Lymphoproliferation

FamilyInfo: Not found

CasePresentingHPOs: HP:0001744, HP:0002716, HP:0002783, HP:0000964, HP:0001873

CaseHPOFreeText: Three affected mutation carriers (including patient) died following alloHSCT due to GvHD. Patient received transplant due to having Thrombocytopenia and widespread lymphoid hyperplasia despite Rituximab. Patient died four months post transplant due to Acute GvHD Grade IV of the gut. See Table S2.

Lymphocytic or granulomatous organ infiltration - patient's brain was affected. Patient received a biopsy and was found to have B Cell and T Cell infiltration. Vaccination response - Tetanus, Pneumococcal vaccination. Respiratory tract involvement, GLILD, Cytopenia, Splenectomy, Autoimmune cytopenia, ITP, Neurological involvement, Dermatological involvement, Coombs.

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, Slatter, et al. PMID: 27102614

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

ClinVarID: N/A

CAID: CA350139018

gnomAD: Not found

SupplementalData: extensive data in S1

Note: Not functionally 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.