ClinGen Dosage Sensitivity Curation Page

FANCB

  • Curation Status: Complete

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Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
15502827 Meetei et al. (2004) detected a 3,314-bp deletion (annotated as 10693del3314) within the FANCB gene that included the promoter region and exon 1, upstream of the translation start site. FANCB cDNA could not be amplified by RT-PCR. Long-range sequencing of genomic DNA was performed to confirm the deletion. The phenotype of the male proband (EUFA178) was reported as Fanconi anemia of complementation group B with growth retardation, skin pigment abnormalities, head abnormalities, radial ray/thumb abnormalities, hypogonadism and thrombocytopenia/anemia. The mother and sister of the proband were carriers; both were shown to have completely skewed X-inactivation of the variant allele. In addition, two males with frameshift variants in FANCB (annotated 1650delT in EUFA1082 and 811insT in EUFA1386) were also identified. All individuals had clinical symptoms of Fanconi anemia (growth retardation, radial ray/thumb abnormalities, hypogonadism and thrombocytopenia/anemia) and a positive chromosomal breakage test.
29232005 Watanabe et al (2017) detected by WES and MLPA an exon 3 deletion in FANBC in a male infant with VACTERL-H association (hydrocephalus, tetralogy of Fallot, absence of pulmonary valve, tracheoesophageal fistula, esophageal atresia, bilateral radial aplasia, left renal dysplasia, duodenal atresia, imperforate anus and cleft vertebrae). Chromosome breakage studies were not reported. The mother and maternal grandmother were carriers. X-inactivation patterns in female carriers were not reported.
21910217 McCauley et al (2011) detected a deletion of exons 8-10 in FANCB in a male with VACTERL-H and a positive chromosome breakage test. The mother was a carrier with skewed X-inactivation. In addition, two related patients with a canonical splice site variant (c.2165+1G>T), two related patients with a 2 base pair deletion (c.1857_1858del,p.Arg619fs), and one patient with a nonsense variant (c.2150T>G,p.Leu717*) were reported. All cases showed skewed maternal X-inactivation and VACTERL-H phenotypes.
16679491 Holden et al. (2006) found a splice site mutation (annotated as IVS7DS+5G-A) in intron 7 of the FANCB gene in a fetus with Fanconi anemia who presented with the VACTERL-H phenotype. Chromosome breakage testing was positive. Similar phenotypes were present in a stillborn male fetus borne by his maternal grandmother. Sequencing of the mutant cDNA fragment from the affected fetus showed that this mutation caused skipping of exon 7 and a frameshift with a stop codon at position 446. The mother and maternal grandmother were heterozygous for the mutation and showed preferential X-inactivation of the mutant FANCB allele.
Jung et al (2019) summarize 21 individuals from the International Fanconi Anemia Registry (IFAR) with FANCB variants, including 3 large deletions, 2 splicing defects, 4 nonsense, 1 duplication, 5 indel and 6 missense variants. The origin of the variants was inherited in 12, de novo in 4 and unknown in 5. Multiple congenital anomalies were present in all, with three or more characteristics of VACTERL-H present in 13 of 15 (87%) individuals with truncating variants, and in 2 of 6 (33%) individuals with missense variants. Functional studies revealed genotype-phenotype correlations linked to the extent of residual FANCD2 monoubiquitination in biochemical or cell-based assays.

Haploinsufficiency phenotype comments:

Hemizygous mutations of FANCB cause X-linked Fanconi anemia of complementation group B (FA-B). The diagnosis of FA is established in a proband with increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC). Most patients with FA have impaired bone marrow function resulting in aplastic anemia and an increased risk of myelodysplastic syndrome or acute myeloid leukemia. Loss-of-function/truncating mutations in FANCB are associated with a more severe phenotype of FA-B and VACTERL-H association, which is characterized by the presence of at least 3 of the 8 following phenotypes: (V) = vertebral abnormalities, (A) = anal atresia, (C) = cardiac (heart) defects, (T) = tracheoesophageal fistula, (E) = esophageal atresia, (R) = renal (kidney) and radial abnormalities, (L) = limb abnormalities, and (H) = hydrocephalus (https://rarediseases.org/rare-diseases/vacterl-with-hydrocephalus/ accessed April 27, 2021). Residual FANCB protein function (for example, in the case of some missense variants) has been associated with a less severe phenotype. Additional evidence: PMID 22052692: Umana et al (2011) detected a 428kb deletion, encompassing the entire FANCB and MOSPD2 genes and part of GLRA2, which was found to be maternally inherited in a male with VACTERL association and Fanconi anemia. PMID 30792206: Mori et al (2019) detected 147kb and 122kb deletions, encompassing the entire FANCB gene and part of the downstream MOSPD2 gene in 2 unrelated Fanconi anemia cases. The two FA-B cases with complete loss of FANCB displayed severe abnormalities, consistent with VACTERL-H association.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Full gene duplication of only FANCB has not been reported in the literature at the time of review.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.