Format

Send to

Choose Destination
J Allergy Clin Immunol. 2016 Oct;138(4):957-969. doi: 10.1016/j.jaci.2016.08.003.

Exome and genome sequencing for inborn errors of immunity.

Author information

1
Department of Immunology and Microbiology, Childhood Immunology, Department of Pediatrics, University Hospitals Leuven and KU Leuven, Leuven, Belgium. Electronic address: Isabelle.Meyts@uzleuven.be.
2
Department of Pediatrics, University Hospitals Leuven and KU Leuven, Leuven, Belgium; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY.
3
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Helix, San Carlos, Calif.
4
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
5
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY.
6
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
7
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
8
Laboratory Medicine, Experimental Laboratory Immunology, Department of Laboratory Medicine, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
9
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Paris, France; Study Center for Immunodeficiency, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
10
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Howard Hughes Medical Institute, New York, NY; Pediatric Hematology and Immunology Unit, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France.

Abstract

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.

KEYWORDS:

Next-generation sequencing; primary immunodeficiency; targeted sequencing; whole-exome sequencing; whole-genome sequencing

PMID:
27720020
PMCID:
PMC5074686
DOI:
10.1016/j.jaci.2016.08.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center