ERCC5 – COFS Syndrome

ERCC5 (XPG) encodes a structure-specific endonuclease essential for the 3’ incision step of nucleotide excision repair. COFS (cerebro-oculo-facio-skeletal) syndrome is a severe, rapidly progressive autosomal recessive neurodevelopmental disorder (MONDO:0008926) characterized by prenatal arthrogryposis, microcephaly, cataracts, growth failure, cerebellar hypoplasia, and ventriculomegaly. Biallelic ERCC5 loss-of-function variants have been implicated in COFS, expanding the spectrum of XPG-related disorders beyond xeroderma pigmentosum and Cockayne syndrome.

In a consanguineous family, linkage and exome sequencing in four affected fetuses identified a homozygous frameshift variant, c.2766dupA (p.Leu923ThrfsTer7), segregating with COFS features including flexion contractures, microcephaly, cerebellar hypoplasia, ventriculomegaly, and hydrops fetalis (PMID:24700531). All four affected sibs were homozygous, and both parents were heterozygous carriers, providing strong segregation evidence.

A second non-consanguineous family demonstrated recurrence of COFS in two siblings with compound heterozygous ERCC5 nonsense variants, c.1096C>T (p.Arg366Ter) and c.2269C>T (p.Arg366Ter), detected prenatally based on ultrasound findings of arthrogryposis and cataract (PMID:33766032). This confirmed autosomal recessive inheritance and recurrence risk in future pregnancies.

Genetically, ERCC5-related COFS is inherited in an autosomal recessive manner with at least six affected individuals reported across two unrelated families and segregation in four sib pairs. The disease-causing alleles are truncating or nonsense mutations predicted to abolish XPG endonuclease function, consistent with a loss-of-function mechanism.

Functionally, XPG mutants lacking catalytic activity (e.g., D812A) fail to support the 3’ incision in dual-incision NER assays, and truncating variants disrupt both incision and protein–protein interactions in the repair complex (PMID:9188507; PMID:10026181). These functional studies align with the severe clinical phenotype observed in COFS cases with ERCC5 loss-of-function.

No studies to date have refuted the ERCC5–COFS association. The concordance of clinical phenotypes, segregation data, and mechanistic disruption of NER underscores a strong gene–disease relationship. Additional cases may further refine genotype–phenotype correlations, but current evidence supports clinical genetic testing of ERCC5 in prenatal presentations of arthrogryposis with ocular and skeletal anomalies.

Key Take-home: Biallelic truncating ERCC5 variants cause autosomal recessive COFS syndrome through loss of XPG endonuclease function, supporting prenatal genetic diagnosis and recurrence risk counseling.

References

• American journal of medical genetics. Part A • 2014 • A novel homozygous ERCC5 truncating mutation in a family with prenatal arthrogryposis--further evidence of genotype-phenotype correlation. PMID:24700531
• BMC medical genomics • 2021 • Prenatal findings of cataract and arthrogryposis: recurrence of cerebro-oculo-facio-skeletal syndrome and review of differential diagnosis. PMID:33766032
• The Journal of biological chemistry • 1997 • The non-catalytic function of XPG protein during dual incision in human nucleotide excision repair. PMID:9188507
• The Journal of biological chemistry • 1999 • Conserved residues of human XPG protein important for nuclease activity and function in nucleotide excision repair. PMID:10026181

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