Clinical, cytogenetic, and molecular insights from 32 years of the Portuguese Fanconi anemia cohort.

PURPOSE: Fanconi anemia (FA) is a rare monogenic chromosome breakage syndrome that presents with 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 and 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 has provided nationwide CI testing since 1993.

RESULTS

Ninety-three FA cases were diagnosed between January 1993 and October 2025; 1 was diagnosed 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% (of 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 hematologic and morphologic phenotypes, observed in 47% of cases. Isolated hematologic and morphologic presentations were observed in 27% and 13% of cases, respectively, while the remaining 13% of patients were asymptomatic.Cytogenetic diagnosis using the standard 1,2,3,4-diepoxybutane test was extremely accurate. Follow-up cytogenetic assessments revealed likely somatic genetic reversals in 2 cases occurring years after the diagnosis, suggesting the importance of reevaluating the 1,2,3,4-diepoxybutane test. CI correlated significantly with the hematologic phenotype and red blood cell analytic parameters.

CONCLUSION

Our data allowed the characterization of the Portuguese FA cohort from clinical, cytogenetic, and molecular perspectives, 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.