Digenic Heterozygous Variants in FANCF and FANCM Disrupt the Fanconi Anemia Pathway in Childhood Leukemia

Germline variants in DNA repair genes play a crucial role in pediatric cancer predisposition. In our TRIO study (n=181), which analyzes exomes of children with cancer and their parents, we identified rare heterozygous digenic variants in Fanconi anemia (FA) pathway genes. As most FA genes are autosomal recessive, single heterozygous variants are not expected to be pathogenic. Here, we specifically investigated one B-ALL patient carrying truncating variants in FANCF and FANCM, each inherited from a parent. To assess their functional relevance, we generated HEK293 cell models using CRISPR-Cas9 mediated knockout of endogenous FANCF/FANCM expression and retroviral overexpression of wild-type and mutant alleles. DNA damage response was analyzed via γH2AX foci after irradiation, and protein interactions were examined through co-immunoprecipitation. Cells with both variants showed impaired DNA repair and altered FA-core complex interactions. These findings support a model in which heterozygous digenic FANCF/FANCM variants disrupt FA signaling and contribute to leukemogenesis. Our data emphasize the need to consider digenic inheritance in cancer genetics and diagnostics.

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Artikel online veröffentlicht:
09. Mai 2025