Genotype–phenotype characterization in 13 individuals with chromosome Xp11.22 duplications

Abstract

We report 13 new individuals with duplications in Xp11.22-p11.23. The index family has one male and two female members in three generations with mild-severe intellectual disability (ID), speech delay, dysmorphic features, early puberty, constipation, and/or hand and foot abnormalities. Affected individuals were found to have two small duplications in Xp11.22 at nucleotide position (hg19) 50,112,063-50,456,458 bp (distal) and 53,160,114-53,713,154 bp (proximal). Collectively, these two regions include 14 RefSeq genes, prompting collection of a larger cohort of patients, in an attempt to delineate critical genes associated with the observed phenotype. In total, we have collected data on nine individuals with duplications overlapping the distal duplication region containing SHROOM4 and DGKK and eight individuals overlapping the proximal region including HUWE1. Duplications of HUWE1 have been previously associated with non-syndromic ID. Our data, with previously published reports, suggest that duplications involving SHROOM4 and DGKK may represent a new syndromic X-linked ID critical region associated with mild to severe ID, speech delay +/- dysarthria, attention deficit disorder, precocious puberty, constipation, and motor delay. We frequently observed foot abnormalities, 5th finger clinodactyly, tapering fingers, constipation, and exercise intolerance in patients with duplications of these two genes. Regarding duplications including the proximal region, our observations agree with previous studies, which have found associations with intellectual disability. In addition, expressive language delay, failure to thrive, motor delay, and 5th finger clinodactyly were also frequently observed in patients with the proximal duplication.

Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease

“…Importantly, this study also performed qPCR and showed that HUWE1 expression levels were elevated in these patient samples, consistent with an overexpression/gain-of-function effect on HUWE1. Subsequent studies that used exome or next generation sequencing identified HUWE1 CNVs in numerous other families with non-syndromic ID [66][67][68][69][70][71][72][73][74][75] (Table 1).…”

“…The most compelling links are to epilepsy or seizure [64,67,[69][70][71][72][73][74]. Autism-like behaviors have also been documented [66,70,72]. While seizure/epilepsy and autism are observed in some individuals with HUWE1 CNVs, the genetic links between HUWE1 and these neurodevelopmental conditions are much less clear and less consistent than ID.…”

A De Novo Xp11.23 Duplication in a Girl with a Severe Phenotype: Expanding the Clinical Spectrum

“…They also reported a 1-year-old boy with a 61-kb duplication at Xp11.23 with global developmental delays, including motor, verbal, and poor feeding. 13 The female presented here had a very small duplication of 175 kb yet had severe ID.…”

Xp11.22 duplications in four unrelated Chinese families: delineating the genotype-phenotype relationship for HSD17B10 and FGD1

“…nonsyndromic ID. To date, 18 unrelated families with overlapping duplications at Xp11.22 have been described, and most patients share similar clinical features, including ID, delayed motor development and delayed language [6][7][8][9][10]. Comparing these duplicated segments, the HUWE1 gene, coding the E3 ubiquitin protein ligase, turned out to be duplicated in all previously described patients.…”

“…Comparing these duplicated segments, the HUWE1 gene, coding the E3 ubiquitin protein ligase, turned out to be duplicated in all previously described patients. Therefore, an increased dosage of HUWE1 is believed to be responsible for nonsyndromic ID [6][7][8][9][10]. To date, little is known about the clinical consequences of other genes involved in this interval, and the genotype-phenotype relationship is still limited.…”