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

Abstract

Although deletions of CHRNA7 have been associated with intellectual disability (ID), seizures and neuropsychiatric phenotypes, the pathogenicity of CHRNA7 duplications has been uncertain. We present the first report of CHRNA7 triplication. Three generations of a family affected with various neuropsychiatric phenotypes, including anxiety, bipolar disorder, developmental delay and ID, were studied with array comparative genomic hybridization (aCGH). High-resolution aCGH revealed a 650-kb triplication at chromosome 15q13.3 encompassing the CHRNA7 gene, which encodes the alpha7 subunit of the neuronal nicotinic acetylcholine receptor. A small duplication precedes the triplication at the proximal breakpoint junction, and analysis of the breakpoint indicates that the triplicated segment is in an inverted orientation with respect to the duplication. CHRNA7 triplication appears to occur by a replication-based mechanism that produces inverted triplications embedded within duplications. Co-segregation of the CHRNA7 triplication with neuropsychiatric and cognitive phenotypes provides further evidence for dosage sensitivity of CHRNA7.

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…1. Additional relevance for the role of a7 nAChRs was recently identified with the finding of triplicate expression of CHRNA7 that is associated with both impairment in cognition and neuropsychiatric phenotypes in a threegeneration pedigree (Soler-Alfonso et al, 2014). These data illustrate that imbalance of the expression levels of a7 nAChRs with either a reduced expression or an excessive expression is associated with neurologic impairment and underscore the need for tight regulation of CHNRA7 expression (Liao et al, 2011;Cubells et al, 2011;Mikhail et al, 2011).…”

“…(D) FISH analysis of another patient reveals a higher signal (see inset) indicative of the triplication of CHRNA7 and illustrates the variability in the chromosomal region 15q13.3. FISH images were kindly provided by Dr. C. Schaaf (see also Schaaf, 2014;Soler-Alfonso et al, 2014).…”

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

“…30,[44][45][46][47][48] In most cases, the triplicated segment is inverted relative to the tandem duplication, and this conformation is known as DUP-TRP/INV-DUP. Breakpoint analysis of six DUP-TRP-DUPs in our study revealed that half of the triplications are in direct orientation and half are inverted relative to the duplication (Table S7).…”

Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

“…13 DUP-TRP/INV-DUP was reported in 20% of the MECP2 CNV gains at Xq28, 13 at the PLP1 locus at Xq22, 14,15 at VIPR2 at 7q36, 16 and at 15q13.3. 17 We investigated the mechanism underlying CGRs found in association with segmental AOH in five families. By using a combined analysis of different high-resolution array platforms and breakpoint junction sequencing, we provide evidence that, in humans, complex rearrangements generated post-zygotically via MMBIR can lead to regional UPD as observed by copy-number-neutral segmental AOH.…”