FANCB – Fanconi Anemia

Fanconi anemia (FA) is a chromosomal instability syndrome characterized by congenital malformations, progressive bone marrow failure, and cancer predisposition. Among the 22 FA genes, FANCB is unique as the only X-linked locus encoding a core complex member essential for FANCD2 monoubiquitination and DNA interstrand crosslink repair. Hemizygous loss-of-function FANCB variants abolish enzymatic activation of FANCD2, leading to the classic FA phenotype in male patients and variable severity depending on residual activity (PMID:32106311). The disease is catalogued as Fanconi anemia and the gene as FANCB.

Inheritance follows an X-linked recessive pattern, with affected males presenting early bone marrow failure and congenital anomalies, and carrier females generally asymptomatic. A cohort of 19 male patients from 16 unrelated families harbored hemizygous truncating or null variants, including c.195dup (p.Thr66fs) (PMID:32106311). These findings provide robust genetic evidence for FANCB involvement in FA.

Segregation analysis is consistent with maternal transmission of pathogenic alleles without affected carrier females. Somatic mosaicism in an FA-B patient with an intragenic duplication demonstrated declining mutation allele fractions over time, correlating with a milder clinical course and confirming pathogenicity of the duplication through FANCD2 ubiquitination assays (PMID:29193904). No additional affected relatives were reported beyond male probands.

Functional studies using transcript analysis, genetic complementation, and biochemical reconstitution have shown that null variants completely abrogate FANCD2 monoubiquitination, while missense variants display a spectrum of residual activity correlating with clinical severity. Complementation of FANCB-null cells with wild-type cDNA restores FA pathway function, supporting a loss-of-function mechanism (PMID:32106311).

Mechanistically, FANCB forms part of the E3 ligase core complex with FANCL and FAAP100, driving FANCD2/FANCI activation. Hemizygous null alleles disrupt this process, causing failure to repair DNA interstrand crosslinks and leading to bone marrow failure and congenital anomalies.

Conflicting evidence arises from a germline FANCB missense alteration p.Gly335Glu identified in head and neck cancer patients, which in fibroblast assays was functionally indistinguishable from wild-type FANCB, underscoring the necessity of functional validation for novel variants (PMID:29491055). This variant does not undermine the overall gene–disease link in FA.

In summary, multiple unrelated probands with hemizygous null FANCB variants, consistent X-linked inheritance, segregation data, and convergent functional assays support a Strong clinical validity classification. The genetic evidence reaches a Strong tier with 19 male probands from 16 families carrying pathogenic alleles, and functional data at a Moderate tier demonstrating rescue of FANCD2 monoubiquitination. FANCB testing enables definitive diagnosis, prenatal counseling, and tailored marrow failure management. Key Take-home: FANCB loss-of-function variants are a clinically actionable cause of X-linked Fanconi anemia with well-established genetic and mechanistic evidence.

References

• Blood • 2020 • Association of clinical severity with FANCB variant type in Fanconi anemia. PMID:32106311
• Molecular genetics & genomic medicine • 2018 • Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype. PMID:29193904
• Anticancer research • 2018 • Mutational and Functional Analysis of FANCB as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas. PMID:29491055

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