A Truncating Variant in the ERCC6 Gene With Three Different Phenotypes: Significant Effects of Modifier Genes

Cockayne syndrome (CS) is a rare, autosomal-recessive, multisystem disorder characterized by microcephaly, failure to thrive, photosensitivity, leukodystrophy, muscle contracture, and intellectual disability. It is caused by deleterious variant in the ERCC6 and ERCC8 genes, which are involved in the transcription-coupled nucleotide excision repair system. According to severity and age of onset, CS is categorized into four types: I, II, III, and cerebrooculofacioskeletal syndrome (COFS). However, some researchers consider COFS to be a distinct disease from CS, while others describe COFS as a severe form of CS.

Whole-exome sequencing (WES) and Sanger sequencing were used to identify potential pathogenic causative variant.

WES data analysis revealed a nonsense variant (NM_000124: c.3862C>T, p.R1288X) in the ERCC6 gene, which was co-segregated using Sanger sequencing. Although this variant has been reported previously in association with both CS and COFS separately, this study's patient manifested intermediate symptoms.

This study's findings expand the clinical spectrum of the variant (NM_000124: c.3862C>T, p.R1288X) and provide more supporting evidence that CS and COFS are phenotypic spectrums rather than different clinical conditions in which genetic and epigenetic factors probably play a pivotal role in the severity of symptoms.