Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders

Abstract

Copy number variations are a common cause of intellectual disability (ID). Determining the contribution of copy number variants (CNVs), particularly gains, to disease remains challenging. Here, we report four males with ID with sub-microscopic duplications at Xp11.2 and review the few cases with overlapping duplications reported to date. We established the extent of the duplicated regions in each case encompassing a minimum of three known disease genes TSPYL2, KDM5C and IQSEC2 with one case also duplicating the known disease gene HUWE1. Patients with a duplication encompassing TSPYL2, KDM5C and IQSEC2 without gains of nearby SMC1A and HUWE1 genes have not been reported thus far. All cases presented with ID and significant deficits of speech development. Some patients also manifested behavioral disturbances such as hyperactivity and attention-deficit/ hyperactivity disorder. Lymphoblastic cell lines from patients show markedly elevated levels of TSPYL2, KDM5C and SMC1A, transcripts consistent with the extent of their CNVs. The duplicated region in our patients contains several genes known to escape X-inactivation, including KDM5C, IQSEC2 and SMC1A. In silico analysis of expression data in selected gene expression omnibus series indicates that dosage of these genes, especially IQSEC2, is similar in males and females despite the fact they escape from X-inactivation in females. Taken together, the data suggest that gains in Xp11.22 including IQSEC2 cause ID and are associated with hyperactivity and attention-deficit/hyperactivity disorder, and are likely to be dosage-sensitive in males.

A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability

“…It has been proposed that non-synonymous variants in this gene are responsible for non-syndromic ID, whereas truncating variants may generate a more severe neurodevelopmental phenotype related to the loss of function of IQSEC2. 5 In agreement with our hypothesis of a dosage effect of the IQSEC2 protein, Moey et al 34 have recently published a review of cases with submicroscopic copy-number gains on Xp11.22 in which they suggest that IQSEC2 gene is a dosagesensitive gene contributing to ID and behavioral disturbances. 34 These authors speculate that increased dosage of IQSEC2 gene may lead to an inappropriate response to glutamate signaling with similar phenotypic consequences as those observed in patients with duplications involving glutamate receptors.…”

“…Regarding clinical features in females, these are less severe due to the presence of a normal X-chromosome, which has been previously described. 9,11 I2 II2 II4 II5 II6 III1 Olson et al 30 Gandomi et al 31 Tran Mau-Them et al 5 Tran Mau-Them et al 5 Gilissen et al 32 33 Moey et al 34 Moey et al 34 Moey et al 34 Moey et al 34 Froyen et al 35 Froyen et al 35 Froyen et al 35 Gedeon et al 36 Froyen et al 37 Froyen et al 37 Froyen et al 37 Froyen et al 37 Patient 1 IQSEC2 splicing mutation and ID I Madrigal et al…”

“…2,5,[30][31][32][33][34][35][36][37][38][39][40][41] Tables 1 and 2 summarize the clinical manifestations of patients with deletions or duplications in the IQSEC2 gene and Table 3 summarizes the clinical manifestations of patients with point variants in this gene. It has been proposed that non-synonymous variants in this gene are responsible for non-syndromic ID, whereas truncating variants may generate a more severe neurodevelopmental phenotype related to the loss of function of IQSEC2.…”

The molecular and phenotypic spectrum of IQSEC2‐related epilepsy

“…21 All the patients had developmental delay/ ID and behavioral abnormalities. 21 All the patients had developmental delay/ ID and behavioral abnormalities.…”

X-chromosome inactivation and escape

“…Specific escape genes have been implicated in mental impairment; for example, KDM5C and IQSEC2 deletions or mutations cause X-linked intellectual disability both in males and females, consistent with dosage sensitivity (Santos-Reboucas et al 2011; Simensen et al 2013; Fieremans et al 2015). Further, cognitive deficiencies have been reported in individuals carrying microduplications of KDM5C and IQSEC2 associated with abnormally high expression (Moey et al 2015). Similarly, mutations and deletions in KDM6A have been discovered in patients with Kabuki syndrome characterized by intellectual disability, growth retardation, skeletal abnormalities, and visceral malformations (Lederer et al 2012; Miyake et al 2012).…”