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FANCE encodes the Fanconi anemia complementation group E protein, a subunit of the FA core complex essential for monoubiquitination and recruitment of the FANCD2–FANCI heterodimer. Loss of FANCE function disrupts DNA interstrand crosslink repair, leading to chromosomal instability, progressive bone marrow failure, congenital anomalies, and cancer predisposition. FANCE is universally implicated in autosomal recessive Fanconi anemia Fanconi anemia.
Biallelic loss-of-function variants in FANCE have been identified in ≥17 unrelated probands ([PMID:11001585]) with autosomal recessive inheritance; segregation in at least 3 families confirms co-segregation of FANCE variants with disease ([PMID:10205272]). A prototypical pathogenic variant, c.396G>A (p.Trp132Ter) (p.Trp132Ter) ([PMID:11001585]), exemplifies nonsense mutations that truncate key C-terminal interaction motifs.
The variant spectrum in FANCE comprises predominantly frameshift and nonsense alleles (≥15 distinct truncating variants) plus essential splice-site and deep-intronic changes identified through complementation cloning and mutation screening ([PMID:11001585], [PMID:10205272]). Recurrent group E mutations have not been noted, reflecting genetic heterogeneity and low allelic founder effect.
Functional assays demonstrate that FANCE directly binds FANCD2 via its extreme C-terminus; disruption of Phe-522 abolishes FANCD2 monoubiquitination and sensitizes cells to mitomycin C ([PMID:24451376]). Complementation of FANCE-deficient cell lines with wild-type but not mutant FANCE restores G2/M checkpoint recovery and DNA repair foci formation. Zebrafish knockout models of fancE recapitulate FA-like hematopoietic defects, confirming conserved function in vivo.
The mechanism of pathogenicity is biallelic loss of FANCE leading to failure of the FA core complex to monoubiquitinate FANCD2–FANCI, blocking interstrand crosslink repair and triggering bone marrow failure. This haploinsufficiency model is supported by both cellular hypersensitivity assays and animal studies.
No robust studies dispute FANCE as an FA gene; monoallelic variants lack high-penetrance cancer risk beyond FA phenotype, and heterozygous carriers do not exhibit FA features or excessive cancer predisposition in large cohorts.
Collectively, FANCE meets criteria for a definitive gene-disease association with Fanconi anemia: numerous unrelated probands, multi-family segregation, and extensive functional concordance. FANCE genetic testing informs diagnosis, guides familial counseling, and underpins future therapeutic development.
Gene–Disease AssociationDefinitive≥17 probands with biallelic FANCE variants, multi-family segregation, functional concordance across cellular and animal models Genetic EvidenceStrong17 distinct LoF variants in unrelated probands; autosomal recessive segregation in ≥3 families Functional EvidenceModerateC-terminal FANCE–FANCD2 interaction critical for monoubiquitination demonstrated by mutagenesis and rescue assays |