ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
20412114 Over 85% of patients with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) have mutations in ENG or ACVRL1. Approximately 10% of these patients have large deletions or duplications. Wooderchak et al. identified a large deletion spanning exons 4?7 of ENG in a patient with clinically confirmed HHT. Using deletion/duplication analysis, the same mutation was found in affected family members. The authors postulated that the formation of the ENG deletions most likely occurred through a non-homologous end-joining (NHEJ) repair. These deletions were confirmed using cDNA sequencing and a custom designed oligo-CGH array.
20414677 Richards-Yutz et al 2010 reported probands that were heterozygous for a deletion of the entire ENG gene. Twenty probands carried partial deletions involving single or multiple exons, and one proband carried a duplication of exons 1 and 2. And most of the probands with intragenic deletion or duplication manifested at least two of three clinical features including pulmonary arteriovenous malformations, epistaxis and telangiectases.
16752392 Bossler et al reported nine exonic deletions in the ENG gene . These individuals (n = 7) were reported to have had three or more HHT criteria. Majority of the probands tested met the criteria for clinical diagnosis of HHT

Haploinsufficiency phenotype comments:

No recurrent mutation hotspots have been observed in ENG, with mutations observed across all coding regions (PMID: 25674101). Severity of the disease seems more profound with deletions of exon 4?7 of ENG.

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

Triplosensitivity phenotype comment:

Rare partial insertions, primarily of exons 2-8, have been associated with the hemorrhagic telangiectasia I (HHT) phenotype, but no focal whole gene duplications of ENG havebeen reported in association with any disorder. Apart from HHT, one study (PMID 27257017) reported large duplications overlapping known haploinsufficiency genes including ENG in patients with a general diagnosis of intellectual disability and developmental delay; but evidence for the triplosensitivity remains to be established. As well, frequency of deletion CNVs spanning ENG is greater vs. duplications based on the expanded CNV morbidity map from children with developmental delay versus healthy controls (PMID: 25217958).