Primary immunodeficiency diseases – genomic approaches delineate heterogeneous Mendelian disorders

Publication date: Available online 16 July 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Asbjørg Stray-Pedersen, Hanne Sørmo Sorte, Pubudu Samarakoon, Tomasz Gambin, Ivan K. Chinn, Zeynep H. Coban Akdemir, Hans Christian Erichsen, Lisa R. Forbes, Shen Gu, Bo Yuan, Shalini N. Jhangiani, Donna M. Muzny, Olaug Kristin Rødningen, Ying Sheng, Sarah K. Nicholas, Lenora M. Noroski, Filiz O. Seeborg, Carla Davis, Debra Canter, Emily M. Mace, Tim Vece, Carl E. Allen, Harshal A. Abhyankar, Phil Boone, Christine R. Beck, Wojciech Krysztof Wiszniewski, Børre Fevang, Pål Aukrust, Geir E. Tjønnfjord, Tobias Gedde-Dahl, Henrik Hjorth-Hansen, Ingunn Dybedal, Ingvild Nordøy, Silje F. Jørgensen, Tore G. Abrahamsen, Torstein Øverland, Anne Grete Bechensteen, Vegard Skogen, Liv T. Osnes, Mari Ann Kulseth, Trine E. Prescott, Cecilie F. Rustad, Ketil R. Heimdal, John W. Belmont, Nicholas Rider, Javier Chinen, Tram Cao, Eric Smith, Maria Soledad Caldirola, Liliana Bezrodnik, Saul Oswaldo Lugo Reyes, Francisco J. Espinosa Rosales, Denisse Guerrero, Luis Alberto Pedroza, Cecilia M. Poli, Jose L. Franco, Claudia M. Trujillo Vargas, Juan Carlos Aldave Becerra, Nicola Wright, Thomas B. Issekutz, Andrew C. Issekutz, Jordan Abbott, Jason W. Caldwell, Diana K. Bayer, Alice Y. Chan, Alessandro Aiuti, Caterina Cancrini, Eva Holmberg, Christina West, Magnus Burstedt, Ender Karaca, Gozde Yesil, Hasibe Artac, Yavuz Bayram, Mehmed Musa Atik, Mohammad K. Eldomery, Mohammad S. Ehlayel, Stephen Jolles, Berit Flatø, Alison A. Bertuch, I. Celine Hanson, Victor W. Zhang, Lee-Jun Wong, Jianhong Hu, Magdalena Walkiewicz, Yaping Yang, Christine Eng, Eric Boerwinkle, Richard A. Gibbs, William T. Shearer, Robert Lyle, Jordan S. Orange, James R. Lupski
BackgroundPrimary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes may overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.ObjectiveTo investigate the ability of whole-exome screening methods to detect disease-causing variants in individuals with PIDDs.MethodsIndividuals with PIDDs from 278 families from 22 countries were investigated using whole-exome sequencing (WES). Computational CNV prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic copy number variants (CNVs). Analytic approaches initially focused on 475 known or candidate PIDD genes, but were non-exclusive and were further tailored based upon clinical data, family history and immunophenotyping.ResultsA likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on the molecular findings. Twelve PIDD-causing CNVs were detected, including seven smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays.ConclusionThis high-throughput genomic approach enabled detection of disease-related variants in unexpected genes, permitted detection of low-grade constitutional, somatic and revertant mosaicism, and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

Teaser

Whole-exome sequencing and CNV screening underlines the genetic component of PIDDs. Revised clinical diagnosis in half and altered management in a quarter of the families emphasizes the relevance of a molecular diagnosis.


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