BAD Oncology Monarch without MONDO or MP 0020119 ClinGen Genome Dosage Map
ClinGen Dosage Sensitivity Curation Page

Xp11.22 region (includes HUWE1)

  • Curation Status: Complete
  • id: ISCA-46299
  • Date last evaluated: 2018-11-19
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 0
  • ClinGen Triplosensitivity Score: 3


Location Information

  • Xp11.22
  • GRCh37/hg19 chrX: 53,363,456-53,793,054
  • View: NCBI | Ensembl | UCSC

GRCh37/hg19 chrX: 53,363,456-53,793,054 ()

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

Haploinsufficiency phenotype comments:

No published descriptions of deletions of this full region yet. This region contains gene HUWE1. For HUWE1, 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 severe LOF may be lethal.

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 score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
22840365 Froyen et al. (2012) expand their characterization of Xp11.22 duplications in individuals with ID (includes cases from Froyen et al. 2008 PMID:18252223). Twelve cases are described with duplications including the entire HUWE1 gene and at least one additional gene on Xp11.22. The minimum region of overlap is chrX:53484944-53712957(GRCh37). These duplications segregated with disease in all families in all individuals tested. Carrier females are described as asymptomatic, with skewed X-inactivation reported in some females. The genome position is defined based on three smallest overlapping duplications seen in patients FAM3, A049 and SB1. Although even smaller partial HUWE1 duplications including only HUWE1 exon 29 to the 3' region were reported in this paper, (and similar duplication reported in other papers as well), those duplications did not segregate with ID phenotype in at least three families. Though there are other genes in the region, HUWE1 is proposed by these authors to be the most likely candidate gene, as expression analysis revealed copy-number-dependent increased mRNA levels in affected patients compared to control individuals.
20655035 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.
26692240 Grams et al. (2016) reported duplications overlapping the proximal region including HUWE1 (including other genes) in 8 individuals with mild?severe intellectual disability, speech delay, dysmorphic features, early puberty, constipation, and/or hand and foot abnormalities. Among those 8 individuals, two brothers (patient 11 and 12) carrying maternally inherited duplication (chrX:53,548,808?54,062,110), including the entire HUWE1 gene and partial adjacent gene PHF8, were reported with speech delay, dysmorphic features, and developmental delay and other similar presentations. This duplication is overlapping with the region we defined based on Froyen 2012 paper. PHF8 is known to associate with ID phenotype. Another duplication (chrX:53,558,765?53,620,255 in patient 10) was reported in a 1-year-old male with history of global developmental delays including motor, verbal, and poor feeding coordination. Family history was limited due to social history. This duplication is smaller and within the region we defined. However, similar duplications were reported as polymorphic, non-segregating with phenotype in Froyen 2012 paper.

Triplosensitivity phenotype comment:

Froyen 2012 paper is the major resource for curation. The duplications are nonrecurrent, and mediated by different mechanisms, so it is hard to determine the genome position. Although the common region of all 12 duplications is chrX:53484944-53712957, a larger region (chrX:53363456-53793054) (GRCh37) that contains three independent cases with duplications were determined as Xp11.22 region (includes HUWE1) with a triplosensitivity score 3. Santos-Rebou?as et al. 2015 (PMID: 25652354) detected two unrelated sporadic individuals with syndromic ID carrying unique overlapping duplications encompassing HUWE1. Duplications are larger than this region, incluing PHF8 and other genes as well. Madrigal et al. (2007) report a duplication of the entire HUWE1 gene in an individual with moderate ID and minor dysmorphic features. The duplication was also found in the proband's affected brother and their unaffected carrier mother, who was shown to have skewed X-inactivation. The duplication was not found in 75 normal male controls. The duplication was found using a BAC-array, therefore, it is not clear whether additional genes, especially the nearly ID related gene PHF8, may be involved in the duplication as well. Grams et al. (2016) reported duplications overlapping the proximal region including HUWE1 (including other genes) in 8 individuals with mild?severe intellectual disability, speech delay, dysmorphic features, early puberty, constipation, and/or hand and foot abnormalities. Among those 8 individuals, two brothers (patient 11 and 12) carrying maternally inherited duplication (chrX:53,548,808?54,062,110), including the entire HUWE1 gene and partial adjacent gene PHF8, were reported with speech delay, dysmorphic features, and developmental delay and other similar presentations. This duplication is overlapping with the region we defined based on Froyen 2012 paper. PHF8 is known to associate with ID phenotype.

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.