Genotype-phenotype correlations in biallelic carriers of FANCM protein truncating variants: A systematic literature review

Abstract

The FANCM gene is involved in the Fanconi Anemia (FA) DNA repair pathway. Although germline biallelic pathogenic variants in genes of this pathway cause the recessive FA syndrome, the role of FANCM in FA or FA-like has been questioned. Biallelic FANCM protein truncating variants (PTVs) have been primarily linked to infertility and cancer, suggesting the gene causes a clinically distinct phenotype. Four literature databases were systematically searched from inception to June 2024 to identify published articles describing individuals carrying biallelic PTVs in FANCM. Twenty articles describing 40 carriers of biallelic FANCM PTVs were identified. We established genotype-phenotype correlations and found that women carrying biallelic combinations of the C-terminal p.Gln1701* and p.Gly1906Alafs*12 PTVs showed infertility, chromosome fragility, breast cancer, and chemotoxicity. Men carrying the same PTVs combinations showed infertility only. Carriers of biallelic combinations including a single N-terminal PTV showed chromosome fragility, infertility, and early onset breast cancer and/or squamous cell carcinoma, and pediatric hematological cancers, often associated with severe chemotoxicity. Our findings indicate that FANCM biallelic PTVs may cause a novel recessive syndrome which is distinct from FA and characterized by infertility, chromosome fragility, cancer and chemotoxicity. While infertility is always observed, the severity of chromosome fragility, cancer predisposition and chemotoxicity seem to depend on FANCM PTVs position and the sex of the carrier. Larger analyses are warranted to consolidate these findings.