Complex Segmental Duplications Mediate a Recurrent dup(X)(p11.22-p11.23) Associated with Mental Retardation, Speech Delay, and EEG Anomalies in Males and Females

Abstract

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

Next-Generation Sequencing of Duplication CNVs Reveals that Most Are Tandem and Some Create Fusion Genes at Breakpoints

“…Regions that are enriched in paralogous segmental duplications or interspersed repeats give rise to more duplications via NAHR. 49,59 We detected three duplications flanked by pairs of Alu repeats that are 75%-88% identical and that generate a hybrid Alu at the breakpoint junction (Table S1). Similar homology has been described for other Alu-Alu recombination events that give rise to interstitial deletions and duplications.…”

335.4kb microduplication in chromosome band Xp11.2p11.3 associated with developmental delay, growth retardation, autistic disorder and dysmorphic features

“…Linkage studies also associate this gene-rich and rearrangement-prone interval to several neurogenetic disorders (Hamel et al, 1999;Qiao et al, 2008;Ropers and Hamel, 2005). The importance of genes mapping in this cytobands is underscored by the cause-effect study of microdeletions, microduplications (Chung et al, 2011;Giorda et al, 2009), gene disruption (Kleefstra et al, 2004;Shoichet et al, 2003) or mutations (Freude et al, 2004;Jensen et al, 2005;Kalscheuer et al, 2003;Shoichet et al, 2003) detected in affected patients, but not in healthy male subjects.…”

“…A partial skewed inactivation was effectively detected, but the ratio was not high enough to be considered significant (76:24). Even if a skewed X-inactivation is observed in some healthy mothers of affected patients harbouring an X-linked rearrangement, it is not an always present finding: in some cases, the normal X chromosome inactivation pattern (50%) was sufficient to result in a healthy phenotype (Giorda et al, 2009). …”

“…In some cases (Giorda et al, 2009;Minks et al, 2008) a certain level of skewed X-inactivation was detected in the carrier mothers of children affected by X-linked pathologies, as a consequence of a cellular negative selection. This hypothesis was investigated also in our patient's mother by means of a methylation assay performed on DNA extracted by peripheral blood.…”

“…Furthermore, this region is involved in rearrangements with recurrent breakpoints, mediated by a recombination between flanking complex segmental duplications (Giorda et al, 2009). The region involved in the duplication described here is smaller and flanking, but does not correspond to the recurrent breakpoints.…”