Methods: We performed whole exome sequencing (WES) of 256 families with PIDD. Variants of interest were identified in an unbiased manner using several criteria: 1) known or predicted PIDD-causing genes; 2) appropriate segregation; 3) minor allelic frequency; 4) phylogenetic conservation; 5) prediction for damage; 6) tissue expression; 7) known ability to cause disease relevant to the phenotype; 8) established immunologic function.
Results: Of the 256 families, 63 (25%) had a defect in one or more genes likely to cause the phenotype. Of these 63 cases, 19 (30%) had a variant in two or more PIDD-associated genes. In 4 families, the effect of the second gene mutation was likely masked by the defect in the other gene. In 1 case, distinct features of both molecular defects were present. For 6 cases, phenotypic features appeared to fit only one of the genes. For the remaining 8 cases, the phenotype did not fit the typical presentation of either PIDD-associated gene defect. In these individuals, potential interactions between the genes to produce a merged phenotype remain under investigation. Finally, 9 families with likely molecular diagnoses had one variant in a PIDD-associated gene, an atypical presentation for that gene defect, and other relevant variants in genes with immunologic function not yet reported to cause PIDD.
Conclusions: Patients with PIDDs can have pathogenic variants in multiple genes that may contribute to the phenotype. WES provides insight into uncovering these potential blended phenotypes.