Abstract
Fanconi anemia (FA; OMIM: 227650) is a rare genetic disorder characterized by bone marrow failure, congenital anomalies, and cancer predisposition. While FANCA mutations account for most FA cases, phenotypic overlap with other disorders complicates diagnosis. This study analyzes molecular diagnostic pathways for FANCA-related FA and establishes a hereditary differential diagnosis for ectrodactyly. A Chinese FA family clinical phenotype was collected. The proband and father underwent whole-genome sequencing. Copy number variations (CNVs) in FANCA were assessed by genomic qPCR. Functional characterization of the EHMT1 variant included minigene splicing assays, RT-qPCR and Western blotting on peripheral blood samples. The proband showed pancytopenia and bone marrow hypoplasia, suggesting aplastic anemia. Sequencing analysis identified two FANCA mutations, NM_000135.4: c.154C>T and NC_000016.9: g.89865477_89895212del, which caused partial protein deletion. Subsequent pedigree analysis revealed that the affected individuals of the proband's paternal lineage, who exhibited ectrodactyly, were heterozygous for the EHMT1 c.2382 + 1750G>A variant (NM 024757.5) and showed significantly reduced EHMT1 mRNA expression, demonstrating complete genotype-phenotype co-segregation. Furthermore, Western blot revealed reduced H3K9me2 and decreased intensity of a ∼100 kDa EHMT1-reactive band in the proband's father. The newly identified g.89865477_89895212del mutation enriches the FANCA gene mutant spectrum. Additionally, the EHMT1 c.2382 + 1750G>A variant co-segregates with ectrodactyly and is accompanied by significantly reduced EHMT1 mRNA expression.