RAD51C – Fanconi anemia

RAD51C, a RAD51 paralog essential for homologous recombination (HR)–mediated DNA repair, has been implicated in Fanconi anemia (FA), complementation group O. In 2010, a consanguineous family with multiple affected siblings presenting congenital abnormalities and bone marrow failure was found to harbor a homozygous RAD51C missense variant c.773G>T (p.Arg258Leu) (PMID:20400963). Clinically, these patients exhibited pancytopenia and heightened cellular sensitivity to DNA interstrand cross-linking agents, consistent with FA pathophysiology.

Subsequently, prenatal whole‐exome sequencing identified compound heterozygous RAD51C variants c.571+5G>A and c.935G>A (p.Arg312Gln) in a neonate with FA–like phenotype, including overlapping fingers, cleft lip/palate, and imperforate anus (PMID:29278735). Cellular assays confirmed hypersensitivity to diepoxybutane and mitomycin C, supporting pathogenicity via HR impairment. A third case of a hypermutator fetal genome further underscored defective DNA damage repair associated with biallelic RAD51C variants (PMID:36909564).

Genetic evidence is bolstered by segregation of FA in one family with at least 2 affected relatives, and by three probands across independent families demonstrating biallelic RAD51C mutations. Population data reveal no healthy individuals homozygous for these variants. The inheritance mode is autosomal recessive, and a single representative pathogenic allele c.773G>T (p.Arg258Leu) has been reported in multiple FA cases.

Functional studies in Rad51C-deficient vertebrate cells and DT40 mutants show spontaneous chromosomal aberrations, defective RAD51 focus formation, and severe HR defects upon exposure to cross-linking agents (PMID:11283264). Direct assays in hamster cells documented a reduction in spontaneous HR events in RAD51C mutants (PMID:15336628). Concordant replication fork protection defects have been characterized in human cell lines, linking RAD51C loss to FA phenotypes.

No significant conflicting evidence has been reported disputing RAD51C’s role in FA. Monoallelic carriers do not exhibit FA but may have modest cancer risks; however, biallelic mutations consistently result in FA-like syndromes. No refuting studies have challenged the pathogenicity of the key missense and splice variants described.

Integration of genetic and experimental data supports a Mechanism of disease via loss of HR repair and replication fork protection leading to chromosomal instability and bone marrow failure. Additional unpublished cohorts may exist, but current evidence meets ClinGen criteria for a Moderate gene–disease association. Key take-home: Biallelic RAD51C mutations cause FA (group O) through defective HR and replication fork stability, informing genetic testing and management of FA patients.

References

• Nature Genetics • 2010 • Mutation of the RAD51C gene in a Fanconi anemia-like disorder. PMID:20400963
• European Journal of Medical Genetics • 2018 • Expanding the FANCO/RAD51C associated phenotype: Cleft lip and palate and lobar holoprosencephaly, two rare findings in Fanconi anemia. PMID:29278735
• Research Square • 2023 • SNV/indel hypermutator phenotype in biallelic RAD51C variant - Fanconi anemia. PMID:36909564
• Molecular and Cellular Biology • 2001 • Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. PMID:11283264
• DNA Repair • 2004 • Spontaneous homologous recombination is decreased in Rad51C-deficient hamster cells. PMID:15336628

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