Whole exome sequencing (WES) and genetic linkage analysis were carried out in fourteen members of a large family with 39 individuals (Family A, Fig. 1a and Supplementary Notes). Five family members presented with recurrent respiratory tract infections, hypogammaglobulinemia, autoimmune cytopenia, autoimmune enteropathy and granulomatous infiltrative lung disease. Since no perfectly segregating novel mutations could be identified, we performed an affected-only analysis to allow for reduced penetrance of the causative mutation. Here, we identified 27 novel heterozygous mutations in 19 genes, which had not been listed in dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) (Supplementary Fig. 1). A nonsense mutation at position c.105 (C35*) was identified in the first exon of CTLA4 which segregated with disease, which we also found in six members of Family A who were so far considered healthy (I.2, II.2, II.3, II.10, III.5, and III.6) (Fig. 1a, b).
Case#: Family_A_Patient_A.II.9, male, onset at or before the age of 17, death at age 37 years, ethnicity not specified
DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency" or impaired ligand binding by CTLA4 resulting in "a complex syndrome with features of both autoimmunity and immunodeficiency".
FamilyInfo: The Family A pedigree is shown in Figure 1a and includes 39 members and 11 genotype-positive members, of whom 5 are affected.
CasePresentingHPOs: HP:0010444 (Pulmonary insufficiency), HP:0004313 (Decreased circulating antibody level), HP:0001744 (Splenomegaly), HP:0011108 (Recurrent sinusitis), HP:0002837 (Recurrent bronchitis), HP:0000787 (Nephrolithiasis), HP:0032262 (Pulmonary tuberculosis), HP:0032271 (Extrapulmonary tuberculosis), HP:0006532 (Recurrent pneumonia), HP:0025419 (Pulmonary pneumatocele), HP:0030875 (Abnormality of pulmonary circulation), HP:0010976 (B lymphocytopenia), HP:0004313 (Decreased circulating antibody level), HP:0002720 (Decreased circulating IgA level), HP:0002850 (Decreased circulating total IgM)
CaseHPOFreeText: Diagnosis at age 17 was accompanied by hypogammaglobulinemia and splenomegaly. Death at age 37 was due to pulmonary insufficiency. The patient had pulmonary hypertension and clubbing. Lobectomy and lung transplant were performed. Laboratory values included very low B cells and NK cells.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genotyping was performed at the genome-wide level (whole exome sequencing), and additional linkage analysis was performed in this family.
GenotypingMethod: Genotyping was performed by whole exome sequencing as well as genetic linkage analysis with microsatellite markers, linking the disease locus to the D2S1384 marker on chromosome 2 (close to CTLA4).
PreviouslyPublished: No prior article is known to contain information on the same proband.
Variant: The patient harbors the NM_005214.5(CTLA4):c.105C>A (p.Cys35Ter) variant in the heterozygous state.
ClinVar: 161112
CAID: N/A (Not required, as there is already a ClinVar ID for this variant)
gnomAD: This variant was not found in gnomAD v.2.1.1.
SupplementalData: Yes, the description of the patient is located in the Supplementary Notes, while the clinical phenotypes and laboratory measurements are found in Tables S1 and S2.