Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

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• 作者：Asbjø ; rg Stray-Pedersen ; MD ; PhD^a ; ^b ; ^c ; ^d ; ^e ; ^&lowast ; ; ^{astraype@ous-hf.no} ; Hanne Sø ; rmo Sorte ; MS^f ; ^g ; ^&lowast ; ; Pubudu Samarakoon ; MS^f ; ^g ; Tomasz Gambin ; PhD^a ; ^h ; Ivan K. Chinn ; MD^b ; ^c ; ⁱ ; Zeynep H. Coban Akdemir ; PhD^a ; Hans Christian Erichsen ; MD ; PhD^e ; Lisa R. Forbes ; MD^b ; ^c ; ⁱ ; Shen Gu ; PhD^a ; Bo Yuan ; PhD^a ; ^j ; Shalini N. Jhangiani ; MS^a ; ^j ; ^k ; Donna M. Muzny ; MS^a ; ^j ; ^k ; Olaug Kristin Rø ; dningen ; PhD^f ; Ying Sheng ; PhD^f ; Sarah K. Nicholas ; MD ; PhD^b ; ^c ; ⁱ ; Lenora M. Noroski ; MD ; MPH^c ; ⁱ ; Filiz O. Seeborg ; MD ; MPH^c ; ⁱ ; Carla M. Davis ; MD^c ; ⁱ ; Debra L. Canter ; MS^c ; ⁱ ; Emily M. Mace ; PhD^b ; ^c ; Timothy J. Vece ; MDⁱ ; Carl E. Allen ; MD ; PhDⁱ ; ^l ; ^m ; Harshal A. Abhyankar ; MSⁱ ; ^l ; ^m ; Philip M. Boone ; MD ; PhD^a ; ^j ; Christine R. Beck ; PhD^a ; ^j ; Wojciech Wiszniewski ; MD ; PhD^a ; ^j ; Bø ; rre Fevang ; MD ; PhD^g ; ⁿ ; På ; l Aukrust ; MD ; PhD^g ; ⁿ ; Geir E. Tjø ; nnfjord ; MD ; PhD^g ; ^o ; Tobias Gedde-Dahl ; MD ; PhD^o ; Henrik Hjorth-Hansen ; MD ; PhD^p ; ^q ; Ingunn Dybedal ; MD ; PhD^o ; Ingvild Nordø ; y ; MD ; PhD^g ; ⁿ ; Silje F. Jø ; rgensen ; MDⁿ ; Tore G. Abrahamsen ; MD ; PhD^e ; ^g ; Torstein Ø ; verland ; MD^e ; Anne Grete Bechensteen ; MD ; PhD^e ; Vegard Skogen ; MD ; PhD^r ; Liv T.N. Osnes ; MD ; PhD^s ; Mari Ann Kulseth ; PhD^f ; Trine E. Prescott ; MD^f ; Cecilie F. Rustad ; MD^f ; Ketil R. Heimdal ; MD ; PhD^f ; John W. Belmont ; MD ; PhD^j ; Nicholas L. Rider ; DO^b ; ^c ; ⁱ ; Javier Chinen ; MD ; PhD^c ; ⁱ ; Tram N. Cao ; MS^b ; ^c ; ⁱ ; Eric A. Smith ; BSc^t ; Maria Soledad Caldirola ; BSc^u ; Liliana Bezrodnik ; MD^u
• 关键词：Primary immunodeficiency disease ; whole-exome sequencing ; copy number variants
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：139
• 期：1
• 页码：232-245
• 全文大小：1767 K
• 卷排序：139

文摘

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 can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.ObjectiveWe sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.MethodsPatients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on 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 molecular findings. Twelve PIDD-causing CNVs were detected, including 7 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.