Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

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dc.contributor.authorStray-Pedersen, Asbjorg
dc.contributor.authorSorte, Hanne Sormo
dc.contributor.authorSamarakoon, Pubudu
dc.contributor.authorGambin, Tomasz
dc.contributor.authorChinn, Ivan K.
dc.contributor.authorAkdemir, Zeynep H. Coban
dc.contributor.authorErichsen, Hans Christian
dc.date.accessioned2020-03-26T19:42:23Z
dc.date.available2020-03-26T19:42:23Z
dc.date.issued2017
dc.departmentSelçuk Üniversitesien_US
dc.description.abstractBackground: 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. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients 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. 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 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. 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.en_US
dc.description.sponsorshipSouth-Eastern Norway Health Authority; American Women's club of Oslo; National Human Genome Research InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); National Heart, Lung, and BloodUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [U54HG006542]; Jeffrey Modell Foundation; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI-120989]en_US
dc.description.sponsorshipFunding for the work performed in Oslo was provided by the South-Eastern Norway Health Authority, and A. S.-P. received research scholarship from the American Women's club of Oslo. The BHCMG is supported by the National Human Genome Research Institute and the National Heart, Lung, and Blood (U54HG006542). Funding was also provided by the Jeffrey Modell Foundation and NIH AI-120989 (to J.S.O.).en_US
dc.identifier.doi10.1016/j.jaci.2016.05.042en_US
dc.identifier.endpage245en_US
dc.identifier.issn0091-6749en_US
dc.identifier.issn1097-6825en_US
dc.identifier.issue1en_US
dc.identifier.pmid27577878en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage232en_US
dc.identifier.urihttps://dx.doi.org/10.1016/j.jaci.2016.05.042
dc.identifier.urihttps://hdl.handle.net/20.500.12395/35403
dc.identifier.volume139en_US
dc.identifier.wosWOS:000393996800025en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMOSBY-ELSEVIERen_US
dc.relation.ispartofJOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGYen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.selcuk20240510_oaigen_US
dc.subjectPrimary immunodeficiency diseaseen_US
dc.subjectwhole-exome sequencingen_US
dc.subjectcopy number variantsen_US
dc.titlePrimary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disordersen_US
dc.typeArticleen_US

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