Whole Exome Sequencing in Inborn Errors of Immunity

Use the Power but Mind the Limits

Giorgia Bucciol; Erika Van Nieuwenhove; Leen Moens; Yuval Itan; Isabelle Meyts


Curr Opin Allergy Clin Immunol. 2017;17(6):421-430. 

In This Article

Choosing the Appropriate Next-generation Sequencing Strategy for Inborn Errors of Immunity

Compared with WGS, WES and targeted panel sequencing have the advantage of being cheaper and of generating a much smaller set of data to analyze;[11,28–30] the drawbacks include an incomplete coverage of the genome (WES misses most intronic mutations and some mutations in nonprotein-coding genes), and technical problems related to the capture step. For targeted panels, the ulterior restriction of the analysis to genes already described in connection with disease is the major limitation. As the rate of description of novel genes causing inborn errors of immunity is now, on average 10/year, gene panels become in fact quickly obsolete.[5] The Mendeliome, a panel covering all known genes causing Mendelian disorders, has been proposed in 2015 as a cheaper and more manageable diagnostic tool compared to WES. However, the same reservations as for targeted panel analysis hold true.[31] For these reasons, from a technical point of view WGS is at present the most reliable approach for the discovery of known and novel mutations in known and novel genes, at the expense of sequencing cost and time needed to analyze the much wider dataset. However, as 85% of mutations generating Mendelian disorders are estimated to be located in coding regions of the genome, WES remains a highly valuable technique both for clinical diagnostics and for the research of novel disease-associated genes.[32] Clinical exome sequencing is now being offered by diagnostic labs over the world. In this setting, a disease-specific panel-like analysis of the exome data is performed and allows for a more efficient approach in genetic diagnosis.