RAD51 – Fanconi Anemia

Heterozygous missense variants in RAD51 have been identified in three unrelated patients with an atypical, autosomal dominant form of Fanconi anemia. The first patient carried c.877G>A (p.Ala293Thr) (PMID:26681308), the second c.725A>G (p.Gln242Arg) (PMID:30907510), and the third c.391A>C (p.Thr131Pro) (PMID:36698515). All arose de novo, with no evidence of familial segregation.

Patient‐derived lymphocytes exhibit hypersensitivity to mitomycin C–induced chromosomal breakage (PMID:30907510), and biochemical assays demonstrate that patient variants act in a dominant‐negative manner to impair RAD51‐mediated homologous recombination and DNA repair (PMID:26681308). These functional data concordantly support a dominant‐negative mechanism underlying the FA‐R subtype.

Key take‐home: De novo heterozygous RAD51 missense mutations define an autosomal dominant FA subtype presenting with developmental anomalies and neurocognitive impairment, underscoring the need to include RAD51 in diagnostic FA gene panels.

References

• Nature communications • 2015 • A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51. PMID:26681308
• American journal of medical genetics. Part A • 2019 • A Japanese patient with RAD51-associated Fanconi anemia. PMID:30907510
• Clinical case reports • 2023 • A novel RAD51 variant resulting in Fanconi anemia identified in an infant with multiple congenital anomalies. PMID:36698515

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