Year: 2025
Type: article
Study design: Case Report
Abstract: Background and Aims: Fanconi anemia (FA) is a rare inherited disorder characterized by congenital anomalies, progressive bone marrow failure, infertility, and increased cancer susceptibility.On a cellular level, mutations in any of the 23 known FA genes result in chromosomal instability and hypersensitivity to DNA crosslinking agents such as mitomycin C (MMC).Hematopoietic dysfunction, particularly pancytopenia and bone marrow failure, typically represents a key diagnostic feature.Here, we describe a 33-year-old woman presenting primarily with infertility due to premature ovarian insufficiency, without additional clinical abnormalitiesmost notably, no hematologic or hematopoietic manifestations.Routine cytogenetic analysis at a fertility clinic revealed multiple metaphases with chromosomal breakages.Whole-exome sequencing identified a homozygous missense variant in FANCE (p.Met99Lys), initially classified as a variant of uncertain significance.This study aimed to classifiy this variant and to evaluate the molecular and functional consequences.Methods: Functional analyses included assessment of MMC sensitivity and FANCD2 monoubiquitylation in patient-derived lymphocytes and lymphoblasts.To further investigate the residual function of the variant, an isogenic FANCE knockout (KO) model was generated, expressing either wild-type FANCE or the FANCE Met99Lys variant.Results: Patient-derived cells exhibited marked MMC sensitivity and absence of FANCD2 monoubiquitylation in whole cell extracts, confirming a diagnosis of FA.Despite this, the patient displayed an unusually mild phenotype with no signs of hematopoietic failure.In the KO cell model, overexpression of FANCE Met99Lys resulted in partial restoration of FANCD2 monoubiquitylation and chromatin localization, albeit at significantly reduced levels compared to wildtype.This residual activity of the overexpressed protein was sufficient to partially rescue MMC sensitivity.Conclusion: The FANCE p.Met99Lys variant retains a partial activity, that likely explains the attenuated clinical presentation and absence of hematopoietic symptoms.Although the patient fulfilled cellular diagnostic criteria for FA, the mild phenotype underscores the diagnostic challenges in such cases and highlights the critical role of functional validation for an accurate interpretation of missense variants.
Source: EJC Paediatric Oncology
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,340
OpenAlex ID: W4415903341
FWCI:
Cites:
Cited by:
Related to: