Details

Autor(en) / Beteiligte

• Meyts, Isabelle, MD, PhD
• Bosch, Barbara, MD
• Bolze, Alexandre, PhD
• Boisson, Bertrand, PhD
• Itan, Yuval, PhD
• Belkadi, Aziz, PhD
• Pedergnana, Vincent, PhD
• Moens, Leen, PhD
• Picard, Capucine, MD, PhD
• Cobat, Aurélie, MD, PhD
• Bossuyt, Xavier, MD, PhD
• Abel, Laurent, MD, PhD
• Casanova, Jean-Laurent, MD, PhD

Titel

Exome and genome sequencing for inborn errors of immunity

Ist Teil von

• Journal of allergy and clinical immunology, 2016-10, Vol.138 (4), p.957-969

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• The advent of next-generation sequencing (NGS) in 2010 has transformed medicine, particularly the growing field of inborn errors of immunity. NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity. Whole-exome sequencing (WES) is presently the most cost-effective approach for research and diagnostics, although whole-genome sequencing offers several advantages. The scientific or diagnostic challenge consists in selecting 1 or 2 candidate variants among thousands of NGS calls. Variant- and gene-level computational methods, as well as immunologic hypotheses, can help narrow down this genome-wide search. The key to success is a well-informed genetic hypothesis on 3 key aspects: mode of inheritance, clinical penetrance, and genetic heterogeneity of the condition. This determines the search strategy and selection criteria for candidate alleles. Subsequent functional validation of the disease-causing effect of the candidate variant is critical. Even the most up-to-date dry lab cannot clinch this validation without a seasoned wet lab. The multifariousness of variations entails an experimental rigor even greater than traditional Sanger sequencing–based approaches in order not to assign a condition to an irrelevant variant. Finding the needle in the haystack takes patience, prudence, and discernment.