Ending A Diagnostic Odyssey: Moving From Exome to Genome to Identify Cockayne Syndrome

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.