期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 138, 期 4, 页码 957-969出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.08.003
关键词
Next-generation sequencing; whole-exome sequencing; whole-genome sequencing; targeted sequencing; primary immunodeficiency
资金
- KOF mandate of the KU Leuven
- Jeffrey Modell Foundation
- Research Mandate of the FWO Vlaanderen
- Research Council of the Catholic University of Leuven
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- University Paris Descartes
- Rockefeller University
- St. Giles Foundation
- European Research Council [ERC-2010-AdG-268777]
- French National Research Agency (ANR) under the Investments for the future'' program [ANR-10-IAHU-01]
- National Institute of Allergy and Infectious Diseases [R37AI095983]
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 genelevel 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.
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