Exome and genome sequencing for inborn errors of immunity

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Exome and genome sequencing for inborn errors of immunity Isabelle Meyts, MD, PhD, Barbara Bosch, MD, Alexandre Bolze, PhD, Bertrand Boisson, PhD, Yuval Itan, PhD, Aziz Belkadi, PhD, Vincent Pedergnana, PhD, Leen Moens, PhD, Capucine Picard, MD, PhD, Aurélie Cobat, MD, PhD, Xavier Bossuyt, MD, PhD, Laurent Abel, MD, PhD, Jean-Laurent Casanova, MD, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 4, Pages 957-969 (October 2016) DOI: 10.1016/j.jaci.2016.08.003 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 NGS: WES and WGS. Starting from the patient's genomic DNA, short fragments are created by means of either sonication or restriction enzymes. A shotgun library is made in which fragments of DNA are fused with adaptors. In WES the coding exome (or another genomic region of interest in targeted capture) is enriched by means of a “capture” step before sequencing. Ideally, each base or each coding region is then read at least 20 times to discriminate sequencing errors from true variants. After the sequencing cycles, the reads are computationally mapped to a reference genome. Differences between the patient's DNA sequence are compared with this reference and “called” as variants. Alterations in the patient's DNA sequence and the reference genome are identified and called as variants. Various calling pipelines are available to call variants (eg, the Genome Analysis Toolkit). TSS, Transcription start site; UTR, untranslated region. Journal of Allergy and Clinical Immunology 2016 138, 957-969DOI: (10.1016/j.jaci.2016.08.003) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Flow diagram from the raw NGS data set to validation of the mutation for FADD deficiency. Bolze et al42 investigated the WES data set for members of a large, consanguineous, multiplex kindred in which biological features of autoimmune lymphoproliferative syndrome were found to be associated with severe bacterial and viral infections, hepatic encephalopathy, and cardiac malformations. The AR genetic hypothesis set the choice of a variant analysis algorithm and allowed the identification of a homozygous missense candidate variant in FADD, encoding the Fas-associated death domain protein. The variant was identified in all patients. The FADD variant was not found in Exome Aggregation Consortium, 1000 Genomes, or the in-house HGID database (minor allele frequency = 0) and had a high CADD score (23.8), exceeding the FADD MSC (5.07). Connectome analysis predicted FADD to be a candidate novel PID gene because it directly interacts with FAS (P = .0006). Functional analysis revealed an impaired type I interferon antiviral response in assessments of the antiviral effect of IFN-α in vesicular stomatitis virus–infected cells. This accounted for the phenotype in vivo and validated the variant as the disease-causing mutation. For clarity, this flow shows only the steps performed to unravel FADD deficiency (in yellow). This flow diagram is applicable to all other genetic hypotheses (white). DN, Double negative; WT, wild-type. Journal of Allergy and Clinical Immunology 2016 138, 957-969DOI: (10.1016/j.jaci.2016.08.003) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Cumulative number of single-gene defects underlying PIDs described since 1980 until now with either conventional molecular techniques or NGS and their mode of inheritance. If inheritance can be either AR or AD for a given gene, the gene is counted in both categories. The initial description of genes indicated in red involved NGS. Many genes have both LOF and hypomorphic mutations; this is not considered separately. A number of genes harbor both GOF and LOF mutations: STAT1, STAT3, and ZAP70. They are not considered separately, except for STAT1, for which mutations with both AR and AD inheritance have been described. Blue, AR inheritance; red, AD inheritance; green, XR inheritance. Pale colors indicate genes discovered by using NGS. Journal of Allergy and Clinical Immunology 2016 138, 957-969DOI: (10.1016/j.jaci.2016.08.003) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions