ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000006.11) (NC_000006.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21643846 Chen et al. (2011) describe two variants affecting splicing (c.601+5G>A [previously observed in Mani et al.] and c.435_438delCCGG in kindreds with apparently isolated familial patent ductus arteriosus. Neither variant was found in the unaffected members of the kindred or in a group of 100 ethnically-matched controls. The authors predicted that these variants would result in loss of function, and performed functional studies in a later publication, Ji et al. (2014) (PMID: 24507797). Studies described in Ji et al. report that "these mutations resulted in loss of transactivation function, which could not be improved by Cpb/p300-interacting transactivator 2. The c.601+5G>A mutated gene did not express any protein, whereas the [truncated protein produced by the] c.435_438delCCGG mutation did not impact the transactivation function activated by the wild-type TFAP2B." The authors concluded that haploinsufficiency was the mechanism by which these variants caused the phenotypes in their respective kindreds.
15684060 Mani et al.characterized two kindreds with Char syndrome . Genotyping in both families revealed linkage to TFAP2B. Kindred K144 resulted in a splice site missense mutation which segregated with the 22 affected memebers with variable features of Char and was compatible with autosomal dominant transmission. Patent ductus arteriosis showed incomplete penetrance whereas the dysmorphic facies and clinodactyly showed evidence of high penetrance. One obligate carrier of this kindred was non-penetrant. Kindred K145 resulted in a splice site missense mutation in 5 affected individuals of the kindred had patent ductus arteriosis, dysmorphic facies and clinodactyly. Both these mutations were absent in 200 unrelated control chromosomes. Additional phenotypes that segregated with the disease causing muttaions were identified. Mutation K144 were found to alter normal splicing using a biochemical splicing assay. This assay demonstrated abnormal splicing - either complete exon skipping or a mixture of properly spliced and abnormal spliced exon products. No assay was performed for the K145 mutation however authors highlighted that there is no doubt that this would disrupt normal splicing.

Haploinsufficiency phenotype comments:

Variants in TFAP2B, resulting in both dominant negative effects and haploinsufficiency, have been associated with Char syndrome. Char syndrome is characterized by patent ductus arteriosus, dysmorphic facial features, and finger anomalies, and exhibits variable expressivity and decreased penetrance. Variants predicted to result in haploinsufficiency have also been reported in individuals with isolated patent ductus arteriosus (PMID: 18752453). For additional information regarding dominant negative variants and Char syndrome, see PMIDs 10802654, 10368122, and 11505339.

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