Exome and genome sequencing for inborn errors of immunity

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

Research output: Contribution to journalReview article

50 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)957-969
Number of pages13
JournalJournal of Allergy and Clinical Immunology
Volume138
Issue number4
DOIs
Publication statusPublished - 1 Oct 2016
Externally publishedYes

Fingerprint

Exome
Immunity
Genome
Genetic Heterogeneity
Penetrance
Patient Selection
Genes
Needles
Alleles
Medicine
Costs and Cost Analysis
Research

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Meyts, I., Bosch, B., Bolze, A., Boisson, B., Itan, Y., Belkadi, A., ... Casanova, J. L. (2016). Exome and genome sequencing for inborn errors of immunity. Journal of Allergy and Clinical Immunology, 138(4), 957-969. https://doi.org/10.1016/j.jaci.2016.08.003

Exome and genome sequencing for inborn errors of immunity. / Meyts, Isabelle; Bosch, Barbara; Bolze, Alexandre; Boisson, Bertrand; Itan, Yuval; Belkadi, Abdelaziz; Pedergnana, Vincent; Moens, Leen; Picard, Capucine; Cobat, Aurélie; Bossuyt, Xavier; Abel, Laurent; Casanova, Jean Laurent.

In: Journal of Allergy and Clinical Immunology, Vol. 138, No. 4, 01.10.2016, p. 957-969.

Research output: Contribution to journalReview article

Meyts, I, Bosch, B, Bolze, A, Boisson, B, Itan, Y, Belkadi, A, Pedergnana, V, Moens, L, Picard, C, Cobat, A, Bossuyt, X, Abel, L & Casanova, JL 2016, 'Exome and genome sequencing for inborn errors of immunity', Journal of Allergy and Clinical Immunology, vol. 138, no. 4, pp. 957-969. https://doi.org/10.1016/j.jaci.2016.08.003
Meyts, Isabelle ; Bosch, Barbara ; Bolze, Alexandre ; Boisson, Bertrand ; Itan, Yuval ; Belkadi, Abdelaziz ; Pedergnana, Vincent ; Moens, Leen ; Picard, Capucine ; Cobat, Aurélie ; Bossuyt, Xavier ; Abel, Laurent ; Casanova, Jean Laurent. / Exome and genome sequencing for inborn errors of immunity. In: Journal of Allergy and Clinical Immunology. 2016 ; Vol. 138, No. 4. pp. 957-969.
@article{d77b30e6b2eb432e92e9b8a03640aa7d,
title = "Exome and genome sequencing for inborn errors of immunity",
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",
author = "Isabelle Meyts and Barbara Bosch and Alexandre Bolze and Bertrand Boisson and Yuval Itan and Abdelaziz Belkadi and Vincent Pedergnana and Leen Moens and Capucine Picard and Aur{\'e}lie Cobat and Xavier Bossuyt and Laurent Abel and Casanova, {Jean Laurent}",
year = "2016",
month = "10",
day = "1",
doi = "10.1016/j.jaci.2016.08.003",
language = "English",
volume = "138",
pages = "957--969",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "4",

}

TY - JOUR

T1 - Exome and genome sequencing for inborn errors of immunity

AU - Meyts, Isabelle

AU - Bosch, Barbara

AU - Bolze, Alexandre

AU - Boisson, Bertrand

AU - Itan, Yuval

AU - Belkadi, Abdelaziz

AU - Pedergnana, Vincent

AU - Moens, Leen

AU - Picard, Capucine

AU - Cobat, Aurélie

AU - Bossuyt, Xavier

AU - Abel, Laurent

AU - Casanova, Jean Laurent

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

KW - Next-generation sequencing

KW - primary immunodeficiency

KW - targeted sequencing

KW - whole-exome sequencing

KW - whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=84992205953&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992205953&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2016.08.003

DO - 10.1016/j.jaci.2016.08.003

M3 - Review article

VL - 138

SP - 957

EP - 969

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 4

ER -