Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies

Genet Med. 2019 Mar;21(3):663-675. doi: 10.1038/s41436-018-0085-6. Epub 2018 Aug 30.

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.

Keywords: Atypical cohesinopathies; Clinical exome sequencing (CES); Cohesin pathway; STAG1; STAG2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Antigens, Nuclear / genetics
  • Biological Variation, Population / genetics*
  • Carrier Proteins / genetics
  • Cell Cycle Proteins / genetics*
  • Child
  • Child, Preschool
  • Chromosomal Proteins, Non-Histone / genetics*
  • Cohort Studies
  • De Lange Syndrome / diagnosis
  • De Lange Syndrome / genetics
  • Exome / genetics
  • Female
  • Gene Frequency / genetics
  • Genetic Heterogeneity
  • Humans
  • INDEL Mutation / genetics
  • Male
  • Mutation
  • Nuclear Proteins / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Proto-Oncogene Proteins / genetics
  • Retrospective Studies
  • Whole Exome Sequencing / methods

Substances

  • Antigens, Nuclear
  • Carrier Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Nuclear Proteins
  • PDS5A protein, human
  • Proto-Oncogene Proteins
  • STAG1 protein, human
  • STAG2 protein, human
  • WAPAL protein, human
  • cohesins