ClinGen Dosage Sensitivity Curation Page

FANCB

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.