MAD2L2 and Fanconi anemia

Fanconi anemia (MONDO:0019391) is an autosomal recessive disorder marked by congenital anomalies, progressive bone marrow failure (HP:0001976), chromosome instability (HP:0000209), and cancer predisposition. Twenty FANC genes encode proteins that cooperate in DNA interstrand crosslink repair. Recently, MAD2L2 (REV7; HGNC:6764) was identified as a novel FA gene, FANCV.

A single patient with severe bone marrow failure harbored biallelic inactivating MAD2L2 variants, consistent with autosomal recessive inheritance and meeting ClinGen genetic case-level data standards for one proband (PMID:27500492). The only reported variant is c.254T>A (p.Val85Glu), predicted to disrupt REV7 function.

No additional affected relatives were described, but complementation studies in patient-derived cells demonstrated increased chromosome breaks and G2/M arrest upon DNA crosslinker exposure, γH2AX and 53BP1 foci accumulation, and elevated p53/p21 activation, all hallmarks of FA cellular defects (PMID:27500492).

Expression of wild-type REV7 in patient cells fully restored normal DNA repair and cell-cycle profiles, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line recapitulated the FA phenotype, fulfilling functional rescue and model system criteria (PMID:27500492).

These data support a loss-of-function mechanism for MAD2L2 in FA, with REV7 required for interstrand crosslink repair and hematopoietic progenitor maintenance. No conflicting reports have emerged to date.

Collectively, the genetic and experimental evidence establishes a strong gene–disease association for MAD2L2 in Fanconi anemia and justifies inclusion of MAD2L2 in FA diagnostic panels and carrier screening for autosomal recessive FA.

References

• The Journal of Clinical Investigation • 2016 • Biallelic inactivation of REV7 is associated with Fanconi anemia. PMID:27500492

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