ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Focal deletions have not been reported in the published literature for this gene, resulting in a haploinsufficiency score of 0 for the gene alone. However, there have been numerous reports of larger 17p13.3 deletions including this gene. YWHAE is thought to be involved in the Miller-Dieker syndrome (MDS) critical region (PMID: 12621583); this phenotype is observed when the deletion also includes the PAFAH1B1 gene. This paper also suggests that inclusion of YWHAE in 17p13.3 deletions involving PAFAH1B1 results in the most severe lissencephaly grade. A separate phenotype has been described in individuals with 17p13.3 deletions that include YWHAE and other genes but NOT PAFAH1B1. Bruno et al. (2010) reported on a series of microdeletions fitting this description, and described the main characteristics of the phenotype as significant postnatal growth retardation, mild to moderate mental retardation and facial dysmorphic manifestations (PMID: 20452996). Some individuals were found to have mild structural abnormalities of the white matter. Enomoto et al. (2012) also report on a 17p terminal deletion including YWHAE but not PAFAH1B1, but report that their proband had a normal brain MRI. The female proband was ascertained due to mild developmental delay, dysmorphic features, and severe growth retardation (PMID: 22887762). Please note that this gene is included within the Miller-Dieker syndrome critical region. Please see this entry for additional details: ISCA-37430

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

Triplosensitivity phenotype comment:

Focal duplications of YHWAE have not been reported in the literature, resulting in a triplosensitivity score of 0. However, there have been several reports of phenotypes associated with larger duplications including YHWAE, including that of macrosomia, mild developmental delay, pervasive developmental disorder, behavioral abnormalities and dysmorphic features (PMID: 19136950; 23035971, PMID: 20452996). Duplications involving YHWAE AND PAFAH1B1 have been associated with moderate to mild developmental and psychomotor delay and hypotonia (PMID: 20452996). Of note: Bruno et al. (2010) reviewed a series of microduplications involving the 17p13.3 region. Of those duplications that did NOT include PAFAH1B1 (deemed in this paper as class I microduplications) and were not interpreted as "benign" by the submitting laboratory, the smallest region of overlap only included YHWAE. The phenotype associated with this group of duplications was described as "autistic manifestations and other behavioural symptoms, speech and motor delay, subtle dysmorphic facial features, subtle hand/foot malformations, and a tendency to postnatal overgrowth." (PMID:20452996).