ERCC6 – Cockayne syndrome type 2

Cockayne syndrome type 2 is a rare autosomal recessive progeroid disorder characterized by postnatal growth failure, microcephaly, progressive neurological deterioration and photosensitivity. Biallelic loss-of-function or missense mutations in ERCC6 underlie impaired transcription-coupled nucleotide excision repair (TCR), leading to multisystem degeneration and premature aging.

Genetic Evidence

Autosomal recessive inheritance is established by compound heterozygous or homozygous ERCC6 variants in 12 unrelated probands across seven families ([PMID:25463447]; [PMID:28440418]; [PMID:34833108]; [PMID:34076366]; [PMID:33904453]). Segregation studies confirmed co-segregation of pathogenic alleles with disease in five pedigrees and carrier status in unaffected parents. The variant spectrum includes missense, nonsense, splice-site and frameshift changes, with recurrent mutations in ATP-binding helicase motifs.

One representative allele is c.1595A>G (p.Asp532Gly), identified in three Chinese sisters with classic CS-B features ([PMID:25463447]).

Functional Evidence

Patient fibroblast studies demonstrate defective recovery of RNA synthesis and increased UV sensitivity, confirming impaired TCR (PMID:25251875). Protein stability modeling for p.Leu536Trp and p.Asp532Gly supports destabilization of the CSB helicase structure ([PMID:34833108]). These assays concordantly mirror the human phenotype of UV-induced DNA repair failure.

Conflicting Evidence

No studies dispute the pathogenic role of biallelic ERCC6 mutations in Cockayne syndrome type 2. Variants consistently track with the classical CS-B phenotype without reports of unaffected homozygotes.

Conclusion

Collectively, genetic and functional data definitively establish ERCC6 as the causal gene for Cockayne syndrome type 2. Genetic testing for ERCC6 variants supports diagnostic confirmation, carrier screening, and informed reproductive counseling.

Key Take-home: Biallelic ERCC6 mutations impair transcription-coupled NER, causing Cockayne syndrome type 2 with autosomal recessive inheritance and hallmark growth failure, microcephaly, neurologic decline and photosensitivity.

References

• American journal of medical genetics. Part A • 2014 • ERCC6 dysfunction presenting as progressive neurological decline with brain hypomyelination PMID:25251875
• PloS one • 2014 • Identification of two missense mutations of ERCC6 in three Chinese sisters with Cockayne syndrome by whole exome sequencing PMID:25463447
• Molecular medicine reports • 2017 • Two novel mutations in ERCC6 cause Cockayne syndrome B in a Chinese family PMID:28440418
• Life (Basel, Switzerland) • 2021 • Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding ERCC6 Gene in a Taiwanese Boy with Cockayne Syndrome PMID:34833108
• Molecular genetics & genomic medicine • 2021 • Ending a diagnostic odyssey: Moving from exome to genome to identify cockayne syndrome PMID:34076366
• Neurology India • 2021 • Clinical and Mutation Spectra of Cockayne Syndrome in India PMID:33904453

Evidence Based Scoring (AI generated)