Clinical, Cytogenetic and Molecular Insights from 32 Years of the Portuguese Fanconi Anemia Cohort

Résumé fourni par la source

Purpose Fanconi anemia (FA) is a rare monogenic chromosome breakage syndrome that presents variable morphologic abnormalities and progressive bone marrow failure. Based on over 30 years of diagnostic experience, our main goal was to describe the Portuguese FA population and assess potential clinical/analytical phenotypic correlations with both molecular variants and chromosome instability (CI). Methods We evaluated the in-house database from the Cytogenetics Laboratory of the School of Medicine and Biomedical Sciences, University of Porto, which provides nation-wide CI testing since 1993. Results Ninety-three FA cases were diagnosed between January 1993 and October 2025, one in the prenatal setting due to severe malformations. Molecular characterization was available for 50 of these cases. Of these, 45 carried FANCA variants in homozygosity or compound heterozygosity, with 38% (Romani ethnicity) harboring the homozygous NM_000135.4:c.295C>T p.(Gln99Ter) founder variant. Five additional cases carried variants in FANCD2, FANCG, FANCJ or PALB2 . The most common clinical presentation comprised both hematological and morphological phenotypes, observed in 47% of cases. Isolated hematological and morphological presentations were observed in 27% and 13% of cases, respectively, while the remaining 13% of patients were asymptomatic. Cytogenetic diagnosis using the standard DEB test was extremely accurate. Follow-up cytogenetic assessment revealed a likely somatic genetic reversal in two cases occurring years after the diagnosis, suggesting the importance of the reevaluation of the DEB test. CI correlated significantly with the hematological phenotype and red blood cell analytic parameters. Conclusion Our data allowed the characterization of the Portuguese FA cohort from a clinical, cytogenetic, and molecular perspective, including the identification of population-specific molecular findings and associations between CI and clinical features. Findings related to cytogenetic assessment proved useful not only for diagnosis but also for FA follow-up and prognostic purposes.

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