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Whole Exome Sequencing Identifies Potential Defects in Multiple Immunodeficiency-Associated Genes in Individual Patients and Families with Primary Immunodeficiency Diseases
Sunday, March 5, 2017: 2:45 PM
Rooms B308-B309 (Georgia World Congress Center, Building B)
Ivan Chinn, MD, , , , , , , , , ,
Rationale: Multiple Mendelian genetic defects in individual primary immunodeficiency disease (PIDD) patients have not yet been fully explored.

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.