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#: Grammatikos_2021_Case 1, female, 35 y.o. (onset) 51 y.o. (report), origin not reported

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: affected younger daughter (case 2), affected son (case 3). 2 brothers of case 1 were affected by Evans syndrome. Another brother was affected by unexplained lymphadenopathy. Deceased brother passed due to eft ventricular fibrosis at age 40. Case 1 also had a niece with recurrent cutaneous ulceration and was a LRBA mutation carrier. The eldest daughter of case 1 developed AML (age 14).

CasePresentingHPOs: HP:0001903, HP:0002716, HP:0001945,HP:0003326, HP:0002829, HP:0031457, HP:0033608, HP:0002110, HP:0001744, HP:0033805, HP:0040312, HP:0002840, HP:0002113, HP:0005479, HP:0010976, HP:0025379, HP:0002922, HP:0001974, HP:0032289, HP:0002321, HP:0002013, HP:0001250, HP:0012534, HP:0001260, HP:0001310 (anaemia, lymphadenopathy, fevers, myalgia, arthralgia, scattered opacification, nodules in lung, bronchiectasis, splenomegaly, non-necrotising granulomas, arthritis of left temporomandibular joint, granulomatous lymphadenitis, migratory infiltrates, decreased IgE, low b-cell count, increased TPO antibodies, increased protein CSF, increased WBC, IgG oligoclonoal pattern, vertigo, vomiting, seizures, right-facial dysesthesia, dysarthria, right-sided dysmetria)

CaseHPOFreeText: mass of 1.4 cm resolving spontaneously behind tibialis posterior tendon. MRI revealed mass in the right middle cerebellar peduncle with surrounding edema. Cellular infiltration by CD4:CD* T cells, plasma cells, microglia (2:1 ratio). Neutrophilic infiltrate of the lymphatic system, EBV-related lymphoprliferation, bile salt malabsorption

CaseNotHPOs: HP:0031693, HP:0005344, HP:0003116 (serum EBV, abnormal carotid ultrasound, abnormal echocardiogram)

CaseNotHPOFreeText: presence of inflammatory markers

CasePreviousTesting: 194 genes associated with immune deficiency, next-gen sequencing. Heterozygous VUS found in LRBA.

GenotypingMethod: confirmation of CTLA4 c.81dup by Sanger sequencing

PreviouslyPublished: not reported

Variant: Heterozygous NM_005214.4(CTLA4):c.81_82insT (p.Leu28fs), Heterozygous NM_006726.4(LRBA):c.6424T>C (p.Phe2142Leu)

ClinVarID: 644629, 1038663

CAID: CA645516071, CA358607456

gnomAD: not found, not found

SupplementalData: Figure S1 shows extensive family history

Case#: Grammatikos_2021_ Case3, male, 17 y.o. (onset) 32 y.o. (report), origin not reported

DiseaseAssertion: CTLA4 Haploinsufficiency

FamilyInfo: Mother and sister affected. Extensive family autoimmune history and pedigree recorded in Figure S1.

CasePresentingHPOs: HP:0100651, HP:0000821, HP:0002315, HP:0002018, HP:0002354, HP:0000458, HP:0001973, HP:0001903, HP:0001744, HP:0025379, HP:0025329, HP:0002922, HP:0001882, HP:0032289, HP:0002275, HP:0033693, HP:0008765, HP:0100827 (type 1 diabetes, hypothyroidism, headaches, nausea, memory impairment, anosmia, autoimmune thrombocytopenia, anaemia, splenomegaly, increased TPO antibodies, increased GAD antibodies, increased protein CSF, increased WBC, IgG oligoclonal pattern, poor coordination, olfactory hallucination, auditory hallucination, lymphocytosis)

CaseHPOFreeText: "Electroencephalography confirmed complex partial seizures arising from the right hemisphere and occurring on a background of mild excess of nonspecific slow and theta activity."

CaseNotHPOs: HP:0002693 (abnormal skull base morphology)

CaseNotHPOFreeText: abnormal nasal endoscopy, abnormal upper endoscopy, abnormal venography

CasePreviousTesting: none

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:c.81_82insT (p.Leu28fs)

ClinVarID: 644629

CAID: CA645516071

gnomAD: not found

SupplementalData: Figure S1 shows extensive family history