Nine patients with Xp22.31 microduplication, cognitive deficits, seizures, and talipes anomalies

Abstract

Comparative genomic hybridization (CGH) arrays have significantly changed the approach to identifying genetic alterations causing intellectual disability and congenital anomalies. Several studies have described the microduplication of Xp22.31, involving the STS gene. In such reports characteristic features and pathogenicity of Xp22.31 duplications remains a subject of debate. Here we present a series of nine previously unreported individuals with Xp22.31 duplications, found through microarray analysis in the course of genetic workup for developmental delay, associated with a combination of talipes anomalies, seizures and/or feeding difficulties. The size of the Xp22.31 duplications ranged from 294 kb to 1.6 Mb. We show a comparison of the breakpoints, inheritance and clinical phenotype, and a review of the literature. This clinically detailed series of Xp22.31 duplication patients provides evidence that the Xp22.31 duplication contributes to a common phenotype.

Microcephaly/Trigonocephaly, Intellectual Disability, Autism Spectrum Disorder, and Atypical Dysmorphic Features in a Boy with Xp22.31 Duplication

“…Other features from that study included 5 patients presenting with an abnormal head circumference, 4 with macrocephaly, and 1 with microcephaly. Esplin et al [2014] reported on 9 patients: DD/ID was observed in all the patients, seizures in 4 (44%), talipes in 3 (33%), and feeding difficulties, ASD, and hypotonia in 2 patients, respectively. A single report from Faletra et al [2011] described a patient with dysmorphic features and neurological involvement including DD/ID, talipes, and hypotonia.…”

Severe Neurological Phenotype in a Girl with Xp22.31 Triplication

“…Currently, there is a debate about the pathogenicity of the Xp22.31 duplication [Li et al, 2010;Furrow et Liu et al, 2011;Faletra et al, 2012;Esplin et al, 2014]. An increasing number of patients with the duplication share a common neurobehavioral phenotype.…”

“…Studies [Li et al, 2010;Furrow et al, 2011;Liu et al, 2011;Esplin et al, 2014] have shown, and these argue against the potential pathogenicity, that the duplication is almost always inherited, usually from the mothers, with the absence of abnormal phenotypes in some carriers, although the possibility of an unnoticed phenotype in carrier parents exists. Regarding the gender of the reported cases, except Furrow et al [2011], who reported only males, the studies of Li et al [2010], Liu et al [2011], and Faletra et al [2012] identified both males and females with no significant gender differences.…”

“…laboratories but are challenging to interpret [Shaffer et al, 2007;Li et al, 2010;Furrow et al, 2011;Liu et al, 2011;Faletra et al, 2012;Esplin et al, 2014]. This recurrent duplication contains 4 known genes, PUDP , STS , VCX , and PNPLA4 as well as 2 microRNAs, MIR651 and MIR4767.…”

“…There is a high incidence of this duplication in clinical cases referred for array comparative genomic hybridization (aCGH) and ascertained due to neurobehavioral abnormalities, but the duplication is also observed in the general population. In the majority of clinical cases, it is inherited from a parent, most of them clinically unaffected [Li et al, 2010;Furrow et al, 2011;Liu et al, 2011;Faletra et al, 2012;Esplin et al, 2014]. The duplication may predispose to disease, but the manifestation may require additional genetic and/or environmental factors.…”