Xp11.22 region (includes HUWE1) |
- 0
Haplo
Score - 3
Triplo
Score
Dosage Sensitivity Summary (Region)
Haploinsufficiency (HI) Score Details
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 (TS) Score Details
- X-linked syndromic intellectual disability Monarch
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PUBMED: 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.
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PUBMED: 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.
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PUBMED: 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.
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.