Patients with Primary Immunodeficiencies (PIDs) may suffer from increased susceptibility to infection, autoinflammation, autoimmunity, or lymphoproliferation. The broad range of clinical manifestations, the large number of known defects, and the complexity of diagnostic procedures complicate the accurate diagnosis of PIDs. We applied whole exome sequencing (WES) to detect mutations in patients with PID.
WES was performed on 369 individuals from 350 families with a high rate (>70% ) of consanguineous marriage. Analysis focused on >300 known or candidate PID genes. Candidate genes were further identified based on clinical data, family history, and immunophenotyping. Confirmation of WES findings was done by another method (Sanger sequencing, MLPA, Gene scan assay).
Disease-causing mutations were identified in 207 (59%) families, whereas no molecular explanation could be recognized in 143 (41%) families. In most of the cases (~80%) mutations were novel, and mainly found in DOCK8 (n=13), ATM (n=10), RAG1 (n=9), WAS (n=6), RAB27A (n=6), ADA (n=6), and IL12RB1 (n=6) genes. Mutations in other PID-causing genes such as JAK3, UNC13D, NCF1, LRBA, RAG2, RFXANK, HAX1, STK4 were found in ≤5 patients each. Novel mutations were found in 2 recently described genes (OTULIN & RASGRP1) and several novel candidate genes were identified. Follow-up segregation was done in >80% of the families.
WES is a cost-effective way to screen for known PID genes and a powerful tool to discover novel PID-causing genes. It allows for early and accurate diagnosis, thereby improving treatment decisions and the quality of life of PID patients.