Systematic genetic analysis of pediatric patients with autoinflammatory diseases

Monogenic autoinflammatory diseases (AID) encompass a growing group of inborn errors of the innate immune system causing unprovoked or exaggerated systemic inflammation. Diagnosis of monogenic AID requires an accurate description of the patients' phenotype, and the identification of highly pene...

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Published in:	Frontiers in genetics Vol. 14; p. 1065907
Main Authors:	Poker, Yvonne, von Hardenberg, Sandra, Hofmann, Winfried, Tang, Ming, Baumann, Ulrich, Schwerk, Nicolaus, Wetzke, Martin, Lindenthal, Viola, Auber, Bernd, Schlegelberger, Brigitte, Ott, Hagen, von Bismarck, Philipp, Viemann, Dorothee, Dressler, Frank, Klemann, Christian, Bergmann, Anke Katharina
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 27-01-2023
Subjects:	autoinflammatory diseases FMF genetic diagnostics Genetics inborn errors of immunity (IEI) whole exome sequencing (WES) inborn errors of immunity (IEI) genetic diagnostics whole exome sequencing (WES) FMF autoinflammatory diseases
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Summary:	Monogenic autoinflammatory diseases (AID) encompass a growing group of inborn errors of the innate immune system causing unprovoked or exaggerated systemic inflammation. Diagnosis of monogenic AID requires an accurate description of the patients' phenotype, and the identification of highly penetrant genetic variants in single genes is pivotal. We performed whole exome sequencing (WES) of 125 pediatric patients with suspected monogenic AID in a routine genetic diagnostic setting. Datasets were analyzed in a step-wise approach to identify the most feasible diagnostic strategy. First, we analyzed a virtual gene panel including 13 genes associated with known AID and, if no genetic diagnosis was established, we then analyzed a virtual panel including 542 genes published by the International Union of Immunological Societies associated including all known inborn error of immunity (IEI). Subsequently, WES data was analyzed without pre-filtering for known AID/IEI genes. Analyzing 13 genes yielded a definite diagnosis in 16.0% ( = 20). The diagnostic yield was increased by analyzing 542 genes to 20.8% ( = 26). Importantly, expanding the analysis to WES data did not increase the diagnostic yield in our cohort, neither in single WES analysis, nor in trio-WES analysis. The study highlights that the cost- and time-saving analysis of virtual gene panels is sufficient to rapidly confirm the differential diagnosis in pediatric patients with AID. WES data or trio-WES data analysis as a first-tier diagnostic analysis in patients with suspected monogenic AID is of limited benefit.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Gayane Manukyan, Institute of Molecular Biology (IMB), Armenia Mohamed Tharwat Hegazy, Cairo University, Egypt This article was submitted to Immunogenetics, a section of the journal Frontiers in Genetics Reviewed by: Sylwia Koltan, Nicolaus Copernicus University in Toruń, Poland Edited by: Milena Ivanova Ivanova—Shivarova, Aleksandrovska University Hospital, Bulgaria These authors have contributed equally to this work and share first authorship
ISSN:	1664-8021 1664-8021
DOI:	10.3389/fgene.2023.1065907