Ending a diagnostic odyssey: Moving from exome to genome to identify cockayne syndrome

Jennifer Friedman, Lynne M. Bird, Richard Haas, Shira L. Robbins, Shareef A. Nahas, David P. Dimmock, Matthew J. Yousefzadeh, Mariah A. Witt, Laura J. Niedernhofer, Shimul Chowdhury

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Background: Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross-complementation group 6 (ERCC6 OMIM: *609413) is the gene most frequently mutated in CS. Methods: A child with pre and postnatal growth failure and progressive neurologic deterioration with multisystem involvement, and with nondiagnostic whole-exome sequencing, was screened for causal variants with whole-genome sequencing (WGS). Results: WGS identified biallelic ERCC6 variants, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of ERCC6 mRNA and protein expression, normal unscheduled DNA synthesis, and impaired recovery of RNA synthesis in patient fibroblasts following UV-irradiation. Conclusion: The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify noncoding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing.

Original languageEnglish (US)
Article numbere1623
JournalMolecular Genetics and Genomic Medicine
Issue number7
StatePublished - Jul 2021

Bibliographical note

Funding Information:
This study was supported by the Rady Children's Hospital and the National Institute of Child Health and Human Development and National Human Genome Research Institute (U19 HD077693) and the National Institute of Environmental Health Sciences (U01 ES029603). SLR is supported in part by an unrestricted grant from the Research to Prevent Blindness, New York, NY. MJY is supported by the Irene Diamond Fund/American Federation on Aging Research Postdoctoral Transition Award.

Publisher Copyright:
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.


  • DNA repair
  • ERCC6
  • cockayne syndrome
  • whole-genome sequencing


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