Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies



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.

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This study was supported in part by the National Human Genome Research Institute/National Heart, Lung, and Blood Institute (NHGRI/NHLBI) grant UM1HG006542 to the BHCMG; and National Institutes of Neurological Disorders and Stroke (NINDS) grant R35 NS105078-01 to JRL. JEP was supported by the NHGRI grant K08 HG008986. AHC, ELB and LR are supported by Newlife (Ref:16-17/12). We acknowledge Dr. Sureni V. Mullegama for critical comments on this manuscript. This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from and via e-mail from Funding for the project was provided by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee (REC) approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

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Correspondence to Pengfei Liu PhD.

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Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), formerly the Baylor Miraca Genetics Laboratories (BMGL), which performs chromosomal microarray analysis and clinical exome sequencing. JR, VP, WJ, CS, WB, SWC, AMB, JLS, CE, YY, RX, and PL are employees of BCM and derive support through a professional services agreement with the BG. JRL serves on the Scientific Advisory Board of the BG. JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc., and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The other authors declare no conflict of interest. All authors read and approved the final manuscript.

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  • Atypical cohesinopathies
  • Clinical exome sequencing (CES)
  • Cohesin pathway
  • STAG1
  • STAG2

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