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Author Notes:

Corresponding Author: Pengfei Liu, PhD, FACMG, Assistant Professor of Department of Molecular and Human Genetics, Assistant Director of Baylor Genetics, Baylor College of Medicine, 713-798-5122, pengfei.liu@bcm.edu.

We acknowledge Dr. Sureni V. Mullegama for critical comments on this manuscript.

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.

Other authors have no disclosures relevant to the manuscript.


Research Funding:

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.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • Atypical cohesinopathies
  • Clinical exome sequencing (CES)
  • Cohesin pathway
  • STAG1
  • STAG2

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies

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Journal Title:

Genetics in Medicine


Volume 21, Number 3


, Pages 663-675

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2018, American College of Medical Genetics and Genomics.

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