RFWD3 and Fanconi Anemia

The ubiquitin ligase RFWD3 plays a crucial role in the repair of DNA damage through homologous recombination, and emerging evidence supports its involvement in Fanconi anemia. This summary integrates data from case reports, multi‐patient studies, and robust functional experiments to support its clinical relevance. The association has implications for diagnostic decision‑making and potential commercial applications in genetic testing.

In the first report (PMID:28691929), a single child with congenital abnormalities characteristic of Fanconi anemia was found to harbor compound heterozygous mutations in RFWD3. Detailed cellular analyses revealed that mutant cells showed increased sensitivity to DNA cross‑linking agents, increased chromosomal breakage, and cell cycle arrest. These findings provided an initial genetic and functional link between RFWD3 dysfunction and Fanconi anemia.

Building on this, a subsequent report (PMID:38058754) described a 10‑year‑old male with clinical features including failure to thrive, facial dysmorphism, radial ray defects, urogenital anomalies, and thrombocytopenia. The patient was found to carry a homozygous c.1501C>T (p.Arg501Cys) variant in RFWD3, further expanding the clinical spectrum and reinforcing the gene’s contribution to Fanconi anemia phenotypes.

Genetic evidence from these reports is supported by the identification of multiple variant classes. Notably, the variant c.1916T>A (p.Ile639Lys) was reported in the first study and is consistent with a disruption in protein function. While segregation analysis is minimal, the detection of these variants in unrelated individuals with classic Fanconi anemia features supports their pathogenicity (PMID:28691929; PMID:38058754).

Experimental studies further detail the mechanism of pathogenicity. Functional assays demonstrated that RFWD3 mutations result in impaired recruitment to chromatin and defective interaction with replication protein A. These disturbances in homologous recombination were confirmed through both in vitro cellular models and knockout mouse studies, where phenotypes consistent with Fanconi anemia, such as embryonic lethality and organ atrophy, were observed (PMID:28691929).

Although familial segregation data is limited, the convergence of genetic and functional evidence provides a coherent narrative. The combined findings indicate that RFWD3 loss‐of‑function impairs DNA repair processes, thereby contributing to the Fanconi anemia phenotype. Moreover, the evidence from both independent patient reports and experimental validation underscores the gene’s clinical utility.

Key take‑home sentence: Integrating clinical case reports with comprehensive functional data, RFWD3 emerges as an important contributor to Fanconi anemia, highlighting the necessity for its consideration in diagnostic genetic testing panels.

References

• The Journal of clinical investigation • 2017 • Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia PMID:28691929
• Molecular syndromology • 2023 • Further Evidence for RFWD3 Gene Causing Fanconi Anemia Complementation Group W: Detailed Clinical Report of the Second Case in the Literature PMID:38058754

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