FANCB was first reported concerning Fanconi anemia complementation group B, with X-linked inheritance (OMIM:300514), in 2004 (Meetei et al., PMID: 15502827). Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and a high frequency of chromosomal aberrations pointing to a defect in DNA repair. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism and inheritance pattern and phenotypic variability. Therefore, the following disease entities have been lumped, with Fanconi Anemia B, VACTERL association, X-linked, with or without hydrocephalus; VACTERLX (OMIM: 314390), VACTERL association with hydrocephalus (OMIM: 276950). Twelve variants (5 missense,1 in-frame indel, 1 nonsense, and 4 frameshift) have been reported in 12 probands in 3 publications (PMIDs: 15502827, 21910217, 23613520,) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function (LOF). This gene-disease association is also supported by animal models and in vitro functional assays (5 points. PMIDs: 26123487, 26658157, 32106311). The Fancb-/Y male mice resemble the human phenotype of patients with pathogenic variants in FANCB related to Fanconi Anemia, such as hypogonadism, testicular failure and reduced fertility. The cells of the hematopoietic system of Fancb−/Y mice are hypersensitive to DNA cross-linking agent mitomycin C (MMC). In summary, FANCB is definitively associated with Fanconi anemia complementation group B, X-linked inheritance (HP:0001417) recessive (HP:0001419). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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