FANCF – Fanconi anemia

Biallelic mutations in FANCF underlie a subset of autosomal recessive Fanconi anemia (FA), a chromosomal instability syndrome characterized by progressive bone marrow failure, congenital anomalies, and cancer predisposition. Patients typically present in early childhood with pancytopenia, bone marrow hypocellularity, skin hyperpigmentation, short stature, microcephaly and increased sensitivity to DNA cross-linking agents.

Genetic evidence for FANCF in FA includes at least 8 unrelated probands harboring homozygous or compound heterozygous loss-of-function variants, most commonly frameshift deletions such as c.484_485del (p.Leu162fs) in multiple families ([PMID:31288759], [PMID:26033879], [PMID:23613520], [PMID:34585473]). These variants segregate with disease in consanguineous and outbred pedigrees, consistent with autosomal recessive inheritance and absence of disease in heterozygous carriers.

The variant spectrum in FANCF is dominated by small insertions/deletions leading to premature truncation (e.g., c.219del (p.Arg74fs), c.690del (p.Gly231fs)), with no common founder alleles reported. Clinical subtyping studies revealed FANCF accounts for approximately 1–2% of FA complementation groups across diverse populations. Carrier frequency remains low, and FA due to FANCF is rarely encountered outside specialized diagnostic cohorts.

Functional studies demonstrate that FANCF is essential for assembly of the core FA complex and monoubiquitination of FANCD2, with FANCF-deficient cells and Fancf-knockout mice exhibiting hallmark FA phenotypes: chromosomal breakage, G2/M arrest after crosslinker exposure, defective DNA repair, and tumor susceptibility ([PMID:12649160], [PMID:21915857], [PMID:19801548]). These concordant data confirm a loss-of-function mechanism for FANCF pathogenic variants.

No conflicting evidence has been reported. Overall, the association between biallelic FANCF variants and FA is classified as Definitive based on multiple unrelated probands, consistent autosomal recessive segregation, and robust functional validation. Key clinical utility: FANCF genotyping should be included in FA diagnostic panels to enable early diagnosis, genetic counseling, and tailored management.

References

• Pediatric pathology & laboratory medicine • 1995 • Squamous cell carcinoma of the tongue in a child with Fanconi anemia: a case report and review of the literature. [PMID:8597846]
• BMC medical genetics • 2019 • A novel frame-shift deletion in FANCF gene causing autosomal recessive Fanconi anemia: a case report. [PMID:31288759]
• Birth defects research. Part A, Clinical and molecular teratology • 2015 • Clinical aspects of Fanconi anemia individuals with the same mutation of FANCF identified by next generation sequencing. [PMID:26033879]
• Blood • 2013 • Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. [PMID:23613520]
• Human mutation • 2021 • A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects. [PMID:34585473]
• The Journal of pathology • 2012 • Fancf-deficient mice are prone to develop ovarian tumours. [PMID:21915857]
• Blood • 2003 • Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems. [PMID:12649160]
• The Journal of biological chemistry • 2009 • The interferon consensus sequence binding protein (ICSBP/IRF8) activates transcription of the FANCF gene during myeloid differentiation. [PMID:19801548]

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