Primary immunodeficiency diseases – genomic approaches delineate heterogeneous Mendelian disorders

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 Krzysztof 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


Background Primary 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. Objective To investigate the ability of whole-exome screening methods to detect disease-causing variants in individuals with PIDDs. Methods Individuals 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. Results A 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. Conclusion This 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.
Author Asbjørg Stray-Pedersen
Asbjørg Stray-Pedersen,,
, Hanne Sørmo Sorte
Hanne Sørmo Sorte,,
, Pubudu Samarakoon
Pubudu Samarakoon,,
, Tomasz Gambin (FEIT / IN)
Tomasz Gambin,,
- The Institute of Computer Science
, Ivan K. Chinn
Ivan K. Chinn,,
, Zeynep H. Coban Akdemir
Zeynep H. Coban Akdemir,,
, Hans Christian Erichsen
Hans Christian Erichsen ,,
, Lisa R. Forbes
Lisa R. Forbes,,
, Shen Gu
Shen Gu,,
, Bo Yuan
Bo Yuan,,
et al.`
Journal seriesJournal of Allergy and Clinical Immunology, ISSN 0091-6749
Issue year2016
NoOnline 2016
Publication size in sheets4.4
Keywords in EnglishPrimary immunodeficiency disease; whole-exome sequencing; copy number variants
ASJC Classification2403 Immunology; 2723 Immunology and Allergy
ProjectDevelopment of new algorithms in the areas of software and computer architecture, artificial intelligence and information systems and computer graphics . Project leader: Rybiński Henryk, , Phone: +48 22 234 7731, start date 18-05-2015, end date 30-11-2016, II/2015/DS/1, Completed
WEiTI Działalność statutowa
Languageen angielski
PID-GADHMD.pdf 13.23 MB
Score (nominal)50
Score sourcejournalList
ScoreMinisterial score = 50.0, 15-05-2020, ArticleFromJournal
Ministerial score (2013-2016) = 50.0, 15-05-2020, ArticleFromJournal
Publication indicators WoS Citations = 82; GS Citations = 3.0; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 2.338; WoS Impact Factor: 2016 = 13.081 (2) - 2016=12.376 (5)
Citation count*3 (2017-01-12)
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