ClinGen Dosage Sensitivity Curation Page

HUWE1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)

Haploinsufficiency phenotype comments:

Four families are described in Froyen et al. (2012; PMID:22840365) with a partial duplication of HUWE1, which does not segregate with XLID. Functional studies were not provided so it is not known whether these duplication would interfere with HUWE1 function or not. Froyen et al. (2008) also describe 3 families with missense mutations in HUWE1 and XLID, which segregate with disease when tested. It is unclear how these missense mutations fit with the author's hypothesis that triplosensitivity of HUWE1 causes XLID, no functional studies are performed to determine the effect of the mutations on protein function. PMID: 26692240 (2016) also reported a patient (patient 10) carrying partial duplication within HUWE1 gene, with intellectual disability, speech delay, and dysmorphic features. No functional studies were performed. ExAC pLI =1, 46 (2 nonsense variants) LOF mutations in total in gnomAD, 14 LOF mutation (1 nonsense variants) in ExAC. Although, population database suggests its LOF intolerance, there is no neurodevelopmental cases reported in literature with clear evidence of haploinsufficiency.

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.

Triplosensitivity phenotype comment:

Duplications of Xp11.22 including only HUWE1 as the minimum region of overlap have been described in patient cohorts with nonsyndromic XLID and variable additional features including minor dysmorphisms, joint contractures and macrocephaly. However, there are no cases reported with duplication involving only HUWE1 gene. ISCA-46299 Xp11.22 region (includes HUWE1) is created and linked to HUWE1. The additional cases reported with duplication including HUWE1 and other genes are listed below: Whibley et al. (2010) described four affected individuals with duplications of Xp11.22 including HUWE1 and at least one additional gene. Three of those duplications were previously described in Froyen 2008 papers, which were also included in Froyen 2012 papers. The additional new case carries a duplication (chrX: 53 232 828-54 256 595), which is larger and overlapping with the region we defined based on Froyen 2012 paper. Santos-Rebou?as et al. 2015 (PMID: 25652354) detected two unrelated sporadic individuals with syndromic ID carrying unique overlapping duplications encompassing HUWE1. ?Duplication includes more than just HUWE1 gene. Demily et al. 2018 (PMID: 29589274) reported on pathogenic?HUWE1?and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2?duplication.

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.