Gene hunting in the genomic era: Approaches to diagnostic dilemmas in patients with primary immunodeficiencies - 01/08/14

Doi : 10.1016/j.jaci.2013.08.021

Craig Platt, MD, PhD, Raif S. Geha, MD ^{^{∗
These authors contributed equally to this work.}}, Janet Chou, MD ^{^{∗
These authors contributed equally to this work.}}^⁎
Division of Immunology and the Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass

^∗Corresponding author: Janet Chou, MD, Division of Immunology, Boston Children's Hospital, Karp Building, 10th Floor, One Blackfan Circle, Boston, MA 02115.

Abstract

There are more than 180 different genetic causes of primary immunodeficiencies identified to date. Approaches for identifying causative mutations can be broadly classified into 3 strategies: (1) educated guesses based on known signaling pathways essential for immune cell development and function, (2) similarity of clinical phenotypes to mouse models, and (3) unbiased genetic approaches. Next-generation DNA sequencing permits efficient sequencing of whole genomes or exomes but also requires strategies for filtering vast amounts of data. Recent studies have identified ways to solve difficult cases, such as diseases with autosomal dominant inheritance, incomplete penetrance, or mutations in noncoding regions. This review focuses on recently identified primary immunodeficiencies to illustrate the strategies, technologies, and potential pitfalls in finding novel causes of these diseases.

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Key words : Primary immunodeficiencies, whole-genome sequencing, whole-exome sequencing, linkage analysis, homozygosity mapping

Abbreviations used : CMC, ED-ID, HSE, IL-2Rγ, LRBA, MonoMAC, NF-κB, NGS, PID, SCID, SNP, TBK1, TLR3, WAS, WES, WGS

Plan

Educated guess based on known molecular pathways

Unbiased genetic approaches

Autosomal dominant diseases

Diseases caused by mutations in noncoding regions

Diseases caused by structural variations of the genome

Diseases with incomplete penetrance

Conclusions and future directions

	Supported by grants from the National Institutes of Health (AI-076210 and AI094017 to R.S.G. and 1 K12 HD052896-01A1 to J.C.), the Dubai Harvard Foundation for Medical Research (R.S.G.), the Jeffrey Modell Foundation (R.S.G.), and a Manton Foundation Pilot Award (J.C.).
	Disclosure of potential conflict of interest: R. S. Geha has received research support from the National Institutes of Health (NIH), the Jeffrey Modell Foundation, and the Dubai Harvard Foundation. J. Chou has received research support from the Manton Foundation and the NIH. C. Platt declares that he has no relevant conflicts of interest.