Whole-exome sequencing for detecting inborn errors of immunity: overview and perspectives

Abstract

The study of inborn errors of immunity is based on a comprehensive clinical description of the patient's phenotype and the elucidation of the underlying molecular mechanisms and their genetic etiology. Deciphering the pathogenesis is key to genetic counseling and the development of targeted therapy. This review shows the power of whole-exome sequencing in detecting inborn errors of immunity along five central steps taken in whole-exome sequencing analysis. In parallel, we highlight the challenges for the clinical and scientific use of the method and how these hurdles are currently being addressed. We end by ruminating on major areas in the field open to future research.

Keywords: inborn errors of immunity; primary immune deficiencies; whole-exome sequencing.

Figure 1.. Approach to the use of whole-exome sequencing for the detection of inborn errors of immunity.

A schematic overview of the different steps taken during whole-exome sequencing analysis (black boxes) with the challenges identified in recent research that need to be accounted for in future research (blue dashed boxes). AD, autosomal dominant; AR, autosomal recessive; CADD, Combined Annotation Dependent Depletion; DN, dominant negative; GDI, gene damaging index; GOF, gain of function; IEI, inborn errors of immunity; LOF, loss of function; MAF, minor allele frequency; MQ, Mapping Quality; MSC, mutation significance cutoff; RD, read depth; XL, X-linked.