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Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.

ABSTRACT: 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 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.

SUBMITTER: Stray-Pedersen A

PROVIDER: S-EPMC5222743 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.

Stray-Pedersen Asbjørg A Sorte Hanne Sørmo HS Samarakoon Pubudu P Gambin Tomasz T Chinn Ivan K IK Coban Akdemir Zeynep H ZH Erichsen Hans Christian HC Forbes Lisa R LR Gu Shen S Yuan Bo B Jhangiani Shalini N SN Muzny Donna M DM Rødningen Olaug Kristin OK Sheng Ying Y Nicholas Sarah K SK Noroski Lenora M LM Seeborg Filiz O FO Davis Carla M CM Canter Debra L DL Mace Emily M EM Vece Timothy J TJ Allen Carl E CE Abhyankar Harshal A HA Boone Philip M PM Beck Christine R CR Wiszniewski Wojciech W Fevang Børre B Aukrust Pål P Tjønnfjord Geir E GE Gedde-Dahl Tobias T Hjorth-Hansen Henrik H Dybedal Ingunn I Nordøy Ingvild I Jørgensen Silje F SF Abrahamsen Tore G TG Øverland Torstein T Bechensteen Anne Grete AG Skogen Vegard V Osnes Liv T N LTN Kulseth Mari Ann MA Prescott Trine E TE Rustad Cecilie F CF Heimdal Ketil R KR Belmont John W JW Rider Nicholas L NL Chinen Javier J Cao Tram N TN Smith Eric A EA Caldirola Maria Soledad MS Bezrodnik Liliana L Lugo Reyes Saul Oswaldo SO Espinosa Rosales Francisco J FJ Guerrero-Cursaru Nina Denisse ND Pedroza Luis Alberto LA Poli Cecilia M CM Franco Jose L JL Trujillo Vargas Claudia M CM Aldave Becerra Juan Carlos JC Wright Nicola N Issekutz Thomas B TB Issekutz Andrew C AC Abbott Jordan J Caldwell Jason W JW Bayer Diana K DK Chan Alice Y AY Aiuti Alessandro A Cancrini Caterina C Holmberg Eva E West Christina C Burstedt Magnus M Karaca Ender E Yesil Gözde G Artac Hasibe H Bayram Yavuz Y Atik Mehmed Musa MM Eldomery Mohammad K MK Ehlayel Mohammad S MS Jolles Stephen S Flatø Berit B Bertuch Alison A AA Hanson I Celine IC Zhang Victor W VW Wong Lee-Jun LJ Hu Jianhong J Walkiewicz Magdalena M Yang Yaping Y Eng Christine M CM Boerwinkle Eric E Gibbs Richard A RA Shearer William T WT Lyle Robert R Orange Jordan S JS Lupski James R JR

The Journal of allergy and clinical immunology 20160716 1

<h4>Background</h4>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.<h4>Objective</h4>We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.<h4>M ...[more]

PMID: 27577878

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Project description:BackgroundPrevious researches have demonstrated a connection between psychiatric disorders and cardiovascular diseases (CVDs), but the cause-and-effect relationship is still unclear. To that goal, the mendelian randomization (MR) method was used to study the causal link between psychiatric disorders and CVDs.MethodsGenome-wide association studies (GWAS) data were collected for four CVDs, including coronary artery disease (n = 547,261), atrial fibrillation (n = 537,409), heart failure (n = 977,323) and ischemic stroke (n = 440,328). Summary data for four psychiatric disorders, including bipolar disorder (n = 51,710), major depressive disorder (n = 480,359), schizophrenia (n = 127,906) and attention deficit hyperactivity disorder (n = 55,374), came from the Psychiatric Genomics Consortium (PGC). All participants were European. The IVW method was mainly used, and the reliability of the results was increased using sensitivity analyses such as MR-Egger, Cochrane's Q test, MR-PRESSO and leave-one-out.ResultsMR revealed that the attention deficit hyperactivity disorder was linked to an increased risk of atrial fibrillation (OR, 1.085; 95% CI, 1.021-1.153; P = 0.008), heart failure (OR, 1.117; 95% CI, 1.044-1.195; P = 0.001), and ischemic stroke (OR, 1.146; 95% CI, 1.052-1.248; P = 0.002). The schizophrenia was linked to an increased risk of heart failure (OR, 1.035; 95% CI, 1.006-1.066; P = 0.017), but was found to be suggestively inverse associated with coronary artery disease (OR, 0.969; 95% CI, 0.941-0.997; P = 0.03). The major depressive disorder was associated with higher odds of coronary artery disease (OR, 1.109; 95% CI, 1.018-1.208; P = 0.018), while the bipolar disorder was linked to a reduced incidence of coronary artery disease (OR, 0.894; 95% CI, 0.831-0.961; P = 0.002) and heart failure (OR, 0.889; 95% CI, 0.829-0.955; P = 0.001). There were no clear relationships between other psychiatric disorders and CVDs.ConclusionThe results provide genetic proof of a possible causal relationship between psychiatric disorders and CVDs. These results imply that psychiatric disorders may be the cause of some CVDs, and that some abnormal mental states may increase or reduce the likelihood of CVDs, providing guidance for the CVDs prevention.

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Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.

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Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.

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