XRCC2 – Fanconi anemia

Biallelic truncating variants in XRCC2 were identified in a patient presenting with the classic Fanconi anemia triad of bone marrow failure, congenital anomalies, and hypersensitivity to DNA interstrand crosslinking agents. Exome sequencing revealed a homozygous c.643C>T (p.Arg215Ter) variant in XRCC2, defining the FA-U complementation group and representing the only reported FA case attributable to XRCC2 deficiency (PMID:22232082). No additional affected relatives were reported, consistent with autosomal recessive inheritance and absence of segregation data.

Functional studies corroborate the causal role of XRCC2 in Fanconi anemia. Murine Xrcc2 knockout models recapitulate FA-like cellular and organismal phenotypes, including increased chromosome breakage and hypersensitivity to DNA crosslinking agents, while genetic complementation of patient‐derived cells with wild-type XRCC2 restores mitomycin C resistance, corrects G2–M cell cycle accumulation, and normalizes chromosome‐breakage frequencies (PMID:22232082; PMID:27208205). Together, these data establish XRCC2 as FANCU, acting downstream of FANCD2 monoubiquitination in the FA-BRCA pathway.

Key take-home: XRCC2 should be included in genetic testing panels for Fanconi anemia, as biallelic loss-of-function variants cause the FA-U subtype and are actionable for diagnosis and management.

References

• Journal of medical genetics • 2012 • Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation. PMID:22232082
• Journal of medical genetics • 2016 • Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene. PMID:27208205

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