Xp11.22 Microduplications Including HUWE1: Case Report and Literature Review

Abstract

Xp11.22 microduplications have been reported in different patients with X-linked intellectual disability. Comparing the duplicated segments, a minimum region of overlap has been identified. Within this region, only one gene, the HUWE1 gene, coding the E3 ubiquitin protein ligase, turned out to be duplicated in all previously described patients. We provide a review of the literature on this topic, making a comparison not only of genetic aspects, but also of clinical, neurophysiological, and neuroradiological findings. Furthermore, we describe the phenotypic and molecular characterization of a case of intellectual disability in a child carrying one of the smallest Xp11.22 microduplications reported, involving the whole sequence of HUWE1 gene. Unlike previously described cases, our patient's neuroimaging showed abnormal findings; he also experienced one seizure and showed interictal electroencephalogram (EEG) epileptiform abnormalities. Given the fact that HUWE1 duplications and mutations have previously been described in several patients with X-linked cognitive impairment, our findings support the hypothesis that HUWE1 gene might be implicate in the pathogenesis of intellectual disability. Nevertheless, further investigations and a more detailed examination of patients' clinical history are needed to clear up other eventual genotype-phenotype correlations, such as the presence of epilepsy/epileptiform EEG abnormalities.

Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability

“…The Xp11.22 deletions documented in subjects 1–4 did not include any of the Xp11.22 genes whose deficiency has been previously implicated in the development of intellectual disability/developmental delay or whose deficiency has been hypothesized to contribute to neurocognitive disorders based on human studies [1–14,18,19,24–27]. Specifically, SHROOM4 is located telemetric to these deletions and TSPYL2 , KDM5C , IQSEC2 , HUWE1 , PHF8 and FAM120C are located progressively centromeric to these deletions (Table 2).…”

“…A number of pathogenic deletions and duplications involving Xp11.22 have been described in individuals with developmental delay, intellectual disability and/or autism [1–14]. These phenotypes have been attributed to changes in the copy number of several genes including, HUWE1 , KDM5C , IQSEC2 , TSPYL2 , SHROOM4 , PHF8 and FAM120C .…”

X‐linked intellectual disability update 2017

“…Sequence variants in HUWE1 have been associated with Juberg-Marsidi syndrome, Brooks syndrome, Turner XLID-macrocephaly syndrome, and a family in which males had moderate ID and normal facial appearance (Friez et al 2016; Turner et al 1994; Froyen et al 2008). Duplication of HUWE1 , usually associated with a HSD17B10 duplication, has been associated with ID of moderate severity, limited speech or dysarthria, facial dysmorphism (hypertelorism, upslanted palpebral fissures, synophrys, open mouth) and usually normal prenatal and postnatal growth measurements (Froyen et al 2008; Whibley et al 2010; Orivoli et al 2016). Two families (IDX17 and IDX31) had no distinctive dysmorphism and had normal growth.…”

Xp11.2 Duplication in Females: Unique Features of a Rare Copy Number Variation

“…The duplication affecting the Xp11.23p11.22 region is unique even among these specific CNVs of X chromosome. It is very rare occurring in both genders (Kokalj Vokac et al, 2002;Bonnet et al, 2006;Froyen et al, 2008Froyen et al, , 2012Monnot et al, 2008;Giorda et al, 2009;Zou and Milunsky, 2009;Holden et al, 2010;Honda et al, 2010;Broli et al, 2011;Chung et al, 2011;Edens et al, 2011;El-Hattab et al, 2011;Flynn et al, 2011;Nizon et al, 2014;Evers et al, 2015;Grams et al, 2015;Moey et al, 2016;Orivoli et al, 2016;Arican et al, 2018;Wang et al, 2020). Inherited and de novo forms are known, all de novo Xp11.23 duplications in which parent of origin has been determined have been paternally inherited (Deng et al, 1990).…”

“…Based on the cases reported so far, the phenotypic features which develop in males and females affected by duplication of Xp11.23p11.22 are very similar (moderate to severe ID, significant delay of speech development, very specific pattern observed on electroencephalography (Broli et al, 2011) with or without seizures manifestation, and dysmorphic facial features), which is very thought provoking in terms of the pathomechanism. While in boys, the pure increase in gene dose caused by the extra copy may explain the symptoms, the gene dosage assessment in girls is much more complicated due to skewed or random X-inactivation (Bonnet et al, 2006;El-Hattab et al, 2011;Nizon et al, 2014;Orivoli et al, 2016;Wang et al, 2020).…”