Ending a diagnostic odyssey: Moving from exome to genome to identify cockayne syndrome. Issue 7 (2nd June 2021) - Friedman, Jennifer
ABSTRACT: 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. Abstract : Diagnosing rare diseases is quite challenging, especially when the phenotype deviates from what has been previously described and extensive testing including exome sequencing is negative. This study highlights the power of genome sequencing to identify noncoding variants that may be missed by exome sequencing as illustrated by the diagnosis of a child with Cockayne Syndrome found to have a novel upstream intronic ERCC6 variant.