ERCC2 – COFS Syndrome

Cerebro-oculo-facio-skeletal (COFS) syndrome is a rare autosomal recessive neurodevelopmental disorder characterized by prenatal microcephaly, congenital cataracts, microphthalmia, arthrogryposis, severe postnatal growth failure and progressive neurologic decline. It falls within the nucleotide excision repair (NER) disorders spectrum, where genes encoding TFIIH subunits play key roles. Biallelic variants in ERCC2 (XPD) have been implicated in COFS syndrome, linking loss of NER function to the severe COFS phenotype.

Autosomal recessive inheritance is confirmed by compound heterozygosity or homozygosity for ERCC2 variants in all reported cases. Four unrelated probands have been described ([PMID:11443545], [PMID:25716912], [PMID:33733458]). All carried biallelic ERCC2 variants: c.1846C>T (p.Arg616Trp), c.1996C>T (p.Arg666Trp), c.2125A>C (p.Thr709Pro) and c.361-1G>A. Segregation consistent with recessive inheritance was demonstrated by parental carrier status in trio analyses.

Clinical evidence includes the original report of a UV-sensitive COFS case with compound c.1846C>T (p.Arg616Trp) and c.2041G>A (p.Asp681Asn) variants and successful prenatal diagnosis in a triplet pregnancy ([PMID:11443545]). Two Japanese infants with COFS died before age 1 year carrying c.1996C>T (p.Arg666Trp) and a second allele; and a 2021 patient with c.361-1G>A and c.2125A>C (p.Thr709Pro) variants expanded the spectrum to include pilocytic astrocytoma ([PMID:25716912], [PMID:33733458]).

Functional studies indicate that ERCC2 mutations impair helicase activity of the TFIIH complex, abrogating transcription-coupled and global genome NER. XPD-deficient patient cell extracts show reduced post-UV survival and defective UV-induced DNA repair. Yeast complementation assays of XPD variants fail to rescue rad3 null lethality, confirming loss of helicase function.

Mechanistically, ERCC2 variants lead to reduced TFIIH stability and defective NER incision steps, resulting in UV hypersensitivity and failure to resolve transcription-blocking lesions. These findings align with the severe multisystem COFS phenotype and inform prenatal diagnostic approaches and genetic counseling.

Key take-home: Biallelic ERCC2 loss-of-function mutations cause autosomal recessive COFS syndrome through impaired TFIIH-mediated NER; ERCC2 genetic testing is recommended for definitive diagnosis and prenatal screening in at-risk families.

References

• American journal of human genetics • 2001 • Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy. PMID:11443545
• Journal of human genetics • 2015 • Constructive rescue of TFIIH instability by an alternative isoform of XPD derived from a mutated XPD allele in mild but not severe XP-D/CS. PMID:25716912
• Clinical genetics • 2021 • Expansion of the clinical and molecular spectrum of an XPD-related disorder linked to biallelic mutations in ERCC2 gene. PMID:33733458
• Advances in genetics • 2001 • Xeroderma pigmentosum and related disorders: defects in DNA repair and transcription. PMID:11037299

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