Dataset Information

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.

ABSTRACT:

Purpose

Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.

Methods

We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.

Results

Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.

Conclusion

CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

SUBMITTER: Yuan B

PROVIDER: S-EPMC6395558 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.

Yuan Bo B Neira Juanita J Pehlivan Davut D Santiago-Sim Teresa T Song Xiaofei X Rosenfeld Jill J Posey Jennifer E JE Patel Vipulkumar V Jin Weihong W Adam Margaret P MP Baple Emma L EL Dean John J Fong Chin-To CT Hickey Scott E SE Hudgins Louanne L Leon Eyby E Madan-Khetarpal Suneeta S Rawlins Lettie L Rustad Cecilie F CF Stray-Pedersen Asbjørg A Tveten Kristian K Wenger Olivia O Diaz Jullianne J Jenkins Laura L Martin Laura L McGuire Marianne M Pietryga Marguerite M Ramsdell Linda L Slattery Leah L Abid Farida F Bertuch Alison A AA Grange Dorothy D Immken LaDonna L Schaaf Christian P CP Van Esch Hilde H Bi Weimin W Cheung Sau Wai SW Breman Amy M AM Smith Janice L JL Shaw Chad C Crosby Andrew H AH Eng Christine C Yang Yaping Y Lupski James R JR Xiao Rui R Liu Pengfei P

Genetics in medicine : official journal of the American College of Medical Genetics 20180830 3

<h4>Purpose</h4>Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.<h4>Methods</h4>We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.<h4>Results</h ...[more]

PMID: 30158690

Similar Datasets

Project description:BackgroundSarcoidosis is an inflammatory disease characterized by non-caseating granuloma formation in various organs, with several recognized genetic and environmental risk factors. Despite substantial progress, the genetic determinants associated with its prognosis remain largely unknown.ObjectivesThis study aimed to identify the genetic changes involved in sarcoidosis and evaluate their clinical relevance.MethodsWe performed whole-exome sequencing (WES) in 116 sporadic sarcoidosis patients (acute sarcoidosis patients, n=58; chronic sarcoidosis patients, n=58). In addition, 208 healthy controls were selected from 1000 G East Asian population data. To identify genes enriched in sarcoidosis, Fisher exact tests were performed. The identified genes were included for further pathway analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, we used the STRING database to construct a protein network of rare variants and Cytoscape to identify hub genes of signaling pathways.ResultsWES and Fisher's exact test identified 1,311 variants in 439 protein-coding genes. A total of 135 single nucleotide polymorphisms (SNPs) on 30 protein-coding genes involved in the immunological process based on the GO and KEGG enrichment analysis. Pathway enrichment analysis showed osteoclast differentiation and cytokine-cytokine receptor interactions. Three missense mutations (rs76740888, rs149664918, and rs78251590) in two genes (PRSS3 and CNN2) of immune-related genes showed significantly different mutation frequencies between the disease group and healthy controls. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis of the clinical features and mutation loci showed that the missense variant (rs76740888, Chr9:33796673 G>A) of PRSS3 [p=0.04, odds ratio (OR) = 2.49] was significantly associated with chronic disease prognosis. Additionally, the top two hub genes were CCL4 and CXCR4 based on protein-protein interaction (PPI) network analysis.ConclusionOur study provides new insights into the molecular pathogenesis of sarcoidosis and identifies novel genetic alterations in this disease, especially PRSS3, which may be promising targets for future therapeutic strategies for chronic sarcoidosis.

Dataset Information

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.

Purpose

Methods

Results

Conclusion

Publications

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets