Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications

Abstract

Genomic instability is a feature of the human Xp22.31 region wherein deletions are associated with X-linked ichthyosis, mental retardation and attention deficit hyperactivity disorder. A putative homologous recombination hotspot motif is enriched in low copy repeats that mediate recurrent deletion at this locus. To date, few efforts have focused on copy number gain at Xp22.31. However, clinical testing revealed a high incidence of duplication of Xp22.31 in subjects ascertained and referred with neurobehavioral phenotypes. We systematically studied 61 unrelated subjects with rearrangements revealing gain in copy number, using multiple molecular assays. We detected not only the anticipated recurrent and simple nonrecurrent duplications, but also unexpectedly identified recurrent triplications and other complex rearrangements. Breakpoint analyses enabled us to surmise the mechanisms for many of these rearrangements. The clinical significance of the recurrent duplications and triplications were assessed using different approaches. We cannot find any evidence to support pathogenicity of the Xp22.31 duplication. However, our data suggest that the Xp22.31 duplication may serve as a risk factor for abnormal phenotypes. Our findings highlight the need for more robust Xp22.31 triplication detection in that such further gain may be more penetrant than the duplications. Our findings reveal the distribution of different mechanisms for genomic duplication rearrangements at a given locus, and provide insights into aspects of strand exchange events between paralogous sequences in the human genome.

CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree

“…Nevertheless, precedence exist for penetrance of neuropsychiatric traits being related to further in increments of gene dosage; triplications at the STS locus appear to be more penetrant than duplications for a DD/ID-associated phenotype. 14 Triplications are very rare chromosomal rearrangements. 15 In general, the resulting clinical phenotype is consistent with, but more severe than, the duplication of the same locus.…”

“…15 In general, the resulting clinical phenotype is consistent with, but more severe than, the duplication of the same locus. 12,14,[16][17][18] Triplications of genomic loci associated with neurocognitive and neuropsychiatric abnormalities have been described, among others, at 22q11.2, 18 7p11.2, 19 Xq28 encompassing the MECP2 gene, 20 and 7q11.23 at the Williams syndrome critical region. 17 Triplications can, in general, be classified as types I and II, as well as being recurrent or non-recurrent, which relates to the molecular mechanism underlying their formation.…”

Severe Neurological Phenotype in a Girl with Xp22.31 Triplication

“…We have only found 3 triplication cases in the literature, all with developmental delay, and in the 2 male individuals, aggressive behavior with features of ADHD was also described [Liu et al, 2011]. The triplication, as far as we know, has not been identified in the general population reinforcing the potential pathogenicity.…”

“…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.…”