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Ending A Diagnostic Odyssey: Moving From Exome to Genome to Identify Cockayne Syndrome
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  • Jennifer Friedman,
  • Lynne Bird,
  • Richard Haas,
  • Shira Robbins,
  • Shareef Nahas,
  • David Dimmock,
  • Matthew Yousefzadeh,
  • Mariah Witt,
  • Laura Niedernhofer,
  • Shimul Chowdhury
Jennifer Friedman
UCSD
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Lynne Bird
UCSD
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Richard Haas
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Shira Robbins
UCSD
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Shareef Nahas
Rady Children's Insitute for Genomic Medicine
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David Dimmock
Rady Children's Hospital
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Matthew Yousefzadeh
University of Minnesota System
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Mariah Witt
University of Minnesota System
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Laura Niedernhofer
University of Minnesota System
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Shimul Chowdhury
Rady Children's Institute for Genomic Medicine
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Abstract

Cockayne syndrome is an ultra-rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross-complementation group 6 (ERCC6) mutations account for most cases. We report a child with pre- and post-natal growth failure and progressive neurologic deterioration with multi-system involvement who has bi-allelic ERCC6 variants, that were discovered by whole genome sequencing, 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. The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify non-coding 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.

Peer review status:Published

02 Jun 2021Published in Molecular Genetics & Genomic Medicine. 10.1002/mgg3.1623