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Fanconi anemia complementation group D1 (FA-D1) is caused by biallelic pathogenic variants in BRCA2, leading to a severe pediatric bone marrow failure and cancer predisposition syndrome. FA-D1 is inherited in an autosomal recessive manner, with affected individuals demonstrating early-onset malignancies, profound cytopenias, and pronounced treatment toxicity. Genetic testing for BRCA2 in suspected FA cases is critical for diagnosis, family counseling, and tailored therapeutic strategies.
FA-D1 is confirmed by identification of biallelic BRCA2 variants in unrelated families. In one pedigree, three siblings presented with T-cell acute lymphoblastic leukemia, Wilms tumor and medulloblastoma, accompanied by repeated pancytopenia and sepsis; they harbored compound heterozygous frameshift variants including c.9366_9367del (p.Ser3123GlnfsTer26) ([PMID:26657402]). In a second family, a young adult and her deceased sister carried the same missense variant c.7007G>A (p.Arg2336His) and demonstrated discordant phenotypes ranging from classic FA-D1 to adult-onset solid tumors ([PMID:36089892]).
Segregation of these variants with disease in siblings across two families (total probands = 5) provides strong support for pathogenicity. Parental testing confirmed heterozygous carrier status without hematologic abnormalities, consistent with recessive inheritance.
The variant spectrum in FA-D1 includes loss-of-function alleles (two frameshift variants) and at least one hypomorphic missense change that disrupts BRCA2 function. To date, no recurrent founder alleles have been reported in FA-D1 cohorts, reflecting the rarity of biallelic BRCA2 mutations.
BRCA2 encodes a key mediator of homologous recombination and DNA crosslink repair. Lymphoblastoid cells from an adult FA-D1 patient exhibited hypersensitivity to DNA-damaging agents and aberrant RAD51 nuclear foci formation in bone marrow cells, confirming impaired DNA repair ([PMID:36089892]). These findings are concordant with the established role of BRCA2 in maintaining genomic stability and align with the severe clinical phenotype observed.
The combination of recessive segregation in multiple affected siblings, definitive biallelic loss-of-function and missense variants, and functional assays demonstrating homologous recombination defects supports a Strong gene–disease association for BRCA2 and FA-D1. Clinicians should include BRCA2 in FA gene panels and consider early surveillance for malignancies and careful cytotoxic therapy dosing in confirmed patients. Family members heterozygous for BRCA2 variants require cancer risk counseling and appropriate screening protocols.
Key Take-home: Biallelic BRCA2 mutations cause FA-D1; molecular diagnosis enables precise management and informs risk-reduction strategies for heterozygous relatives.
Gene–Disease AssociationStrongFive probands across two unrelated families with autosomal recessive segregation and concordant clinical phenotypes Genetic EvidenceStrongBiallelic variants identified in five affected siblings; segregation confirmed in two pedigrees Functional EvidenceModeratePatient‐derived cell lines exhibit hypersensitivity to DNA damage and defective RAD51 foci formation |