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FANCD2 is a critical component of the Fanconi anemia (FA) DNA repair pathway. Biallelic germline mutations in FANCD2 cause autosomal recessive Fanconi anemia, a disorder characterized by congenital anomalies, progressive bone marrow failure, and cancer predisposition including acute myeloid leukemia and squamous cell carcinomas. FA patients exhibit hypersensitivity to DNA interstrand crosslinking agents due to defective DNA damage response and chromatin binding of the monoubiquitinated FANCD2 protein.
Multiple independent studies have identified 33 probands from 27 unrelated families harboring pathogenic FANCD2 variants, consistent with an autosomal recessive inheritance pattern and absence of disease in heterozygous carriers (PMID:17436244). Segregation analyses in consanguineous and non-consanguineous pedigrees confirm biallelic variant transmission only in affected individuals, with no evidence of autosomal dominant phenotypes.
The FANCD2 variant spectrum includes missense, nonsense, frameshift, splice-site, and deep-intronic alleles. A recurrent frameshift mutation, c.2961_2962del (p.Arg987fs), has been reported in multiple FA-D2 patients and abolishes the C-terminal domain required for chromatin localization. Hypomorphic missense changes such as c.958C>T (p.Gln320Ter) further underscore the critical role of intact FANCD2 protein for pathway function.
Functional assays demonstrate that monoubiquitination at Lys561 and proper nuclear targeting of FANCD2 are essential for DNA crosslink repair. Mutant proteins lacking ubiquitination or proper C-terminal sequences fail to form nuclear foci and cannot rescue mitomycin C sensitivity in FANCD2-deficient cells (PMID:15454491). Drosophila models show that loss of FANCD2 or its E3 ligase FANCL leads to hypersensitivity to crosslinking agents and defective S-phase checkpoints, paralleling human FA-D2 cellular phenotypes (PMID:16860002).
Diagnostic assays such as FANCD2 Western blot reliably distinguish FA-D2 patients by absence of the monoubiquitinated isoform, with >90% sensitivity and 100% specificity in Brazilian cohorts, complementing chromosomal breakage tests and genetic sequencing (PMID:19287902).
No substantial conflicting evidence has emerged to refute the association, and the FA-D2 genotype correlates robustly with phenotype severity and therapeutic response.
Key Take-home: FANCD2 mutations have a definitive association with autosomal recessive Fanconi anemia, supported by extensive genetic and functional evidence, and should be included in diagnostic and carrier screening panels.
Gene–Disease AssociationDefinitiveMultiple unrelated probands (n=33 across 27 families) with biallelic FANCD2 variants and concordant functional studies demonstrating monoubiquitination defect and chromatin binding Genetic EvidenceStrong33 probands from 27 independent families with biallelic FANCD2 pathogenic variants, consistent with autosomal recessive inheritance ([PMID:17436244]) Functional EvidenceStrongMonoubiquitination assays, chromatin localization studies, and rescue experiments in cellular and Drosophila models demonstrate loss-of-function and pathway defects ([PMID:15454491]; [PMID:16860002]) |