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ERCC4 encodes the XPF endonuclease, a critical component of nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. Biallelic loss-of-function or deleterious missense variants in ERCC4 cause Fanconi anemia (FA) subtype FA-Q, an autosomal recessive disorder characterized by progressive bone marrow failure, pancytopenia, skin hyperpigmentation, urogenital abnormalities, and growth retardation.
Two unrelated probands with clinical FA lacking biallelic mutations in canonical FA genes were found to carry compound heterozygous or homozygous ERCC4 variants, including c.689T>C (p.Leu230Pro), c.2065C>A (p.Arg689Ser), c.2371_2398dup (p.Ile800fs), and c.1484_1488del (p.Thr495fs). Introduction of wild-type ERCC4 cDNA into patient-derived cell lines fully rescued mitomycin C hypersensitivity and normalized chromosomal breakage, directly implicating ERCC4 defects in FA pathogenesis ([PMID:23623386]).
The variant spectrum comprises both missense changes affecting conserved nuclease domains and frameshift insertions/deletions predicted to truncate XPF. One recurrent theme is that most biallelic combinations of ERCC4 mutations are embryo lethal, consistent with a heterozygous carrier frequency of approximately 1/288 in population screens ([PMID:24027083]). No founder alleles have been described.
Functional assessment reveals that FA-associated ERCC4 mutations specifically impair ICL repair without markedly compromising NER. Biochemical assays confirm that mutant XPF endonuclease fails to incise ICL substrates, while complementation studies restore interstrand crosslink repair. Structural analyses further show that certain missense variants disrupt the XPF–SLX4 interaction, undermining complex stability and genome maintenance.
No conflicting evidence disputes ERCC4’s role in FA-Q; heterozygous carriers do not manifest FA, and large cohort studies find no increased cancer risk in monoallelic ERCC4 carriers outside of FA contexts ([PMID:24027083]).
Collectively, ERCC4–Fanconi anemia achieves a Strong ClinGen clinical validity classification, supported by Moderate genetic evidence (biallelic variants in two probands with functional validation) and Strong experimental evidence (cellular complementation and mechanistic assays). Inclusion of ERCC4 in FA diagnostic panels enables accurate molecular diagnosis, informs prognosis, and guides genetic counseling.
Key Take-home: Autosomal recessive ERCC4 mutations underlie FA-Q; functional rescue assays confirm pathogenicity, supporting clinical testing and management.
Gene–Disease AssociationStrong2 unrelated probands with biallelic ERCC4 variants, with cell line complementation and ICL repair assays demonstrating causality Genetic EvidenceModerateReports of biallelic missense and frameshift ERCC4 variants in 2 FA-Q patients with functional validation ([PMID:23623386]) Functional EvidenceStrongWild-type ERCC4 cDNA rescues patient cell hypersensitivity and chromosomal instability; structural assays illustrate disrupted ICL repair |