ERCC8 – Cockayne syndrome

Cockayne syndrome (CS) is a rare autosomal recessive neurodegenerative disorder characterized by growth failure, microcephaly, neurological dysfunction, photosensitivity, and premature aging. CS type A (CSA) arises from biallelic mutations in ERCC8, encoding the CSA protein, a critical component of transcription-coupled nucleotide excision repair (TC-NER) ([PMID:19309286]). Loss of ERCC8 function impairs TC-NER, leading to accumulation of transcription-blocking DNA lesions in actively transcribed genes.

Genetic evidence for the ERCC8–Cockayne syndrome association is robust. Across multiple cohorts, biallelic ERCC8 variants have been identified in 23 unrelated probands: eight Brazilian patients from six families ([PMID:16865293]), five patients in a targeted NER gene panel study ([PMID:27004399]), two Iranian consanguineous families ([PMID:34461059]), and eight Tunisian patients including siblings ([PMID:35248096]). Segregation studies in these families confirm autosomal recessive inheritance, with co-segregation of pathogenic alleles in affected relatives.

The variant spectrum includes nonsense, frameshift, splice-site, deep intronic, and structural mutations. A representative mutation is c.300C>G (p.Tyr100Ter), a truncating change in exon 4 that abolishes CSA function and was maternally and paternally inherited in a CSA kindred, enabling prenatal diagnosis ([PMID:19309286]). Other recurrent and founder deletions affecting exon 4 have been observed in Asian populations.

Functional assays corroborate the pathogenicity of ERCC8 variants. A homozygous deep intronic change, c.173+1119G>C, was shown by minigene splicing reporters to activate a cryptic exon, validating its mechanistic impact on CSA transcript processing ([PMID:29422660]). In Vietnamese siblings, rescue experiments in patient fibroblasts demonstrated that expression of wild-type ERCC8 restores DNA repair capacity and cell viability, confirming the deleterious effect of compound heterozygous variants including p.Gly162Arg ([PMID:35748794]).

No conflicting evidence has been reported; all studies consistently implicate ERCC8 loss-of-function in CSA pathogenesis. The ERCC8–Cockayne syndrome gene–disease pair is thus classified as Definitive, with extensive genetic and functional concordance over >10 years.

Key Take-home: Biallelic ERCC8 loss-of-function variants cause Cockayne syndrome type A via impaired transcription-coupled NER, supporting molecular diagnosis, genetic counseling, and prenatal testing.

References

• Genetic testing and molecular biomarkers • 2009 • Prenatal diagnosis of Cockayne syndrome type A based on the identification of two novel mutations in the ERCC8 gene. PMID:19309286
• Journal of human genetics • 2006 • Cockayne syndrome type A: novel mutations in eight typical patients. PMID:16865293
• Orphanet journal of rare diseases • 2016 • Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing. PMID:27004399
• Clinica chimica acta; international journal of clinical chemistry • 2021 • Identification of two novel homozygous mutations in ERCC8 gene in two unrelated consanguineous families with Cockayne syndrome from Iran. PMID:34461059
• Orphanet journal of rare diseases • 2022 • Heterogeneous clinical features in Cockayne syndrome patients and siblings carrying the same CSA mutations. PMID:35248096
• European journal of human genetics : EJHG • 2018 • Deep intronic variation in splicing regulatory element of the ERCC8 gene associated with severe but long-term survival Cockayne syndrome. PMID:29422660
• Molecular genetics & genomic medicine • 2022 • Cockayne syndrome without UV-sensitivity in Vietnamese siblings with novel ERCC8 variants. PMID:35748794

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