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

Abstract

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.

Keywords

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