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


Bo Yuan, Juanita Neira, Davut Pehlivan, Teresa Santiago-Sim, Xiaofei Song, Jill Rosenfeld, Jennifer E Posey, Vipulkumar Patel, Weihong Jin, Margaret P Adam, Emma L Baple, John Dean, Chin-To Fong, Scott E Hickey, Louanne Hudgins, Eyby Leon, Suneeta Madan-Khetarpal, Lettie Rawlins, Cecilie F Rustad, Asbjørg Stray-Pedersen, Kristian Tveten, Olivia Wenger, Jullianne Diaz, Laura Jenkins, Laura Martin, Marianne McGuire, Marguerite Pietryga, Linda Ramsdell, Leah Slattery, DDD Study, Farida Abid, Alison A Bertuch, Dorothy Grange, LaDonna Immken, Christian P Schaaf, Hilde Van Esch, Weimin Bi, Sau Wai Cheung, Amy M Breman, Janice L Smith, Chad Shaw, Andrew H Crosby, Christine Eng, Yaping Yang, James R Lupski, Rui Xiao, Pengfei Liu. Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies. Genetics in medicine : official journal of the American College of Medical Genetics. 2019 Mar;21(3):663-675

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PMID: 30158690

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