ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 11q22.1
  • GRCh37/hg19 chr11: 101,981,192-102,104,154
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr11: 102,109,957-102,233,424
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000011.9) (NC_000011.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24462371 Williamson et al. (2014) described two families with optic fissure closure defects (OFCD) with loss of function (LOF) mutations in YAP1: Family 1305 [c.370c>T(p.Arg124*)] mutation was present in 4 family members affected with coloboma (which is typically due to an OFCD) and inherited from the unaffected grandfather. Family 132 [c.1066G>T(p.Glu356*)] mutation proband presented with bilateral OFCD and is part of a family with an autosomal dominant disorder with OFCDs, cleft lip with or without palate, intellectual disability, hematuria(without renal impairment or dysplasia) and sensorineural hearing loss. All 13 affected members carry the nonsense mutation but present with variable features of the syndrome. LOD score for the segregation of nonsense mutations in family 1305 and 132 was 4.2. Another family has been reported with phenotype similar to Family 132 in which YAP1 mutation could not be identified. No other LOF mutations in YAP1 were detected in 700 non-coloboma exomes in UK10K rare disease group or NHLBI exome sequencing project exome variant server (EVS). The UK10K coloboma exome data did not identify any missense mutation that were not also present in EVS. Array data from 210 individuals with eye malformations identified one individual with bilateral OFCDs and intellectual disability with a 29 Mb de novo deletion (chr11:84,886,352-113,918,790) that included YAP1 as well as 434 other genes. A re-evaluation of 336 unrelated OFCD affected individuals (not overlapped with patients for exome sequencing) identified three missense mutations in YAP1: One did not segregate with the OFCD phenotype, two had no family history of eye malformation or parental follow up. Complete inactivation of YAP1 in mice results in developmental arrest at 8.5 days leading to multisystem defects including yolk sac vasculogenesis and embryonic axis elongation. In mice, site and stage specific expression in mouse embryos shows expression otic vesicle, brain stem, in eye and distal optic cup and overlying surface of ectoderm, brain and in both maxillary and frontonasal components of primary palate. In humans, an attempt to quantify YAP1 in two control lymphoblastoid cell lines (LCL) and LCL from proband in Family 132 was not detectable. Differences in phenotype between the two families was suggested to be caused by alternative transcriptional start site. Mutation in Family 132 was in coding sequence of all transcriptscoming from either TSS. Family 1305 mutation was found in the 5'UTR rather than coding sequence and thus thought to be invisible to NMD. However, they were unable to test differential effect on NMD becuase there was no access to direct cell lines or tissues.

Haploinsufficiency phenotype comments:

Though both families are reported to have colobomas, given the discrepancy in phenotype between the two families reported in Williamson et al. 2014, we are giving this gene a haploinsufficiency score of 1; additional information is needed to clarify the role of this gene in optic fissure closure defects.

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