FANCA – Fanconi Anemia

Fanconi anemia (FA) is a hereditary bone marrow failure syndrome caused by biallelic pathogenic variants in any of >22 FANC genes, with FANCA accounting for 60–65% of cases. The disorder is inherited in an autosomal recessive manner and is defined by congenital anomalies, progressive pancytopenia, chromosomal instability, and cancer predisposition (especially acute myeloid leukemia and squamous cell carcinoma of the head and neck).

Large‐scale genetic studies have established a Definitive association between FANCA and FA. Positional cloning of the FA-A locus mapped FANCA to 16q24.3, accounting for ~60% of FA cohorts (PMID:8896564). Subsequent multi-ethnic registries—111 patients in Israel (PMID:31558676), 68 WES-characterised cases (PMID:31586946), and >350 FA-A patients worldwide—demonstrate high penetrance and concordant genotype-phenotype data.

Genetic evidence is Strong: biallelic FANCA variants have been identified in >400 unrelated probands in diverse populations (e.g., Italian, Japanese, Indian, Tunisian) with a wide spectrum of mutation types, including >100 large intragenic deletions, frameshifts, nonsense, missense, and splice-site changes. The recurrent c.2546delC (p.Ser849PhefsTer27) and c.3720_3724del (p.Glu1240fs) alleles exemplify founder effects in East Asian cohorts (PMID:23067021; PMID:25751062). Segregation of FANCA variants with FA phenotype has been observed in >30 consanguineous pedigrees worldwide.

Functional assays provide Moderate evidence: patient-derived FANCA(His1110Pro) fails to bind FANCC, is not phosphorylated, and cannot rescue mitomycin C sensitivity or nuclear localization in FA-A fibroblasts (PMID:10210316). FANCA missense and splice mutants disrupt the monoubiquitination and chromatin targeting of FANCD2, confirming a loss-of-function mechanism.

Heterozygous carriers of FANCA variants do not show increased cancer risk or FA features, and O/E cancer ratios in FANCA carriers approximate unity (PMID:34906449). This supports a recessive mechanism without dominant-negative effects.

Integration of genetic and functional data confirms that FANCA haploinsufficiency underlies FA-A and guides clinical diagnosis via chromosome breakage tests, genetic counselling, and prenatal testing. Key take-home: Biallelic FANCA variants cause FA-A with high clinical validity and actionable genetic testing implications.

References

• Nature Genetics • 1996 • Positional cloning of the Fanconi anaemia group A gene PMID:8896564
• Haematologica • 2020 • Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population PMID:31558676
• Journal of Medical Genetics • 2020 • Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies PMID:31586946
• Experimental Hematology • 1999 • A patient-derived mutant form of the Fanconi anemia protein, FANCA, is defective in nuclear accumulation PMID:10210316
• Genetics in Medicine • 2022 • Risk of cancer in heterozygous relatives of patients with Fanconi anemia PMID:34906449

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