Structures and molecular mechanisms for common 15q13.3 microduplications involving CHRNA7: benign or pathological?

Abstract

We have investigated four ~1.6-Mb microduplications and 55 smaller 350–680-kb microduplications at 15q13.2–q13.3 involving the CHRNA7 gene that were detected by clinical microarray analysis. Applying high-resolution array-CGH, we mapped all 118 chromosomal breakpoints of these microduplications. We also sequenced 26 small microduplication breakpoints that were clustering at hotspots of nonallelic homologous recombination (NAHR). All four large microduplications likely arose by NAHR between BP4 and BP5 LCRs, and 54 small microduplications arose by NAHR between two CHRNA7-LCR copies. We identified two classes of ~1.6-Mb microduplications and five classes of small microduplications differing in duplication size, and show that they duplicate the entire CHRNA7. We propose that size differences among small microduplications result from preexisting heterogeneity of the common BP4–BP5 inversion. Clinical data and family histories of 11 patients with small microduplications involving CHRNA7 suggest that these microduplications might be associated with developmental delay/mental retardation, muscular hypotonia, and a variety of neuropsychiatric disorders. However, we conclude that these microduplications and their associated potential for increased dosage of the CHRNA7-encoded α7 subunit of nicotinic acetylcholine receptors are of uncertain clinical significance at present. Nevertheless, if they prove to have a pathological effects, their high frequency could make them a common risk factor for many neurobehavioral disorders.

Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders

“…21 ASDs have been reported in 4/11 patients with small CHRNA7 duplications referred for chromosomal microarray analysis; however, its pathogenicity remains controversial. 22,23 Recently, Williams et al 24 reported association of the CHRNA7 duplication with attention-deficit hyperactivity disorder. Interestingly, in contrast to patient 4, his brother, who has the SNX19 deletion but not the CHRNA7 duplication, does not present problems with concentration.…”

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

“…In fact, at least six classes of microduplications, varying in size from 350 kb to 1.6 Mb, were shown to arise involving pre-existing heterogeneous inverted BP4 and BP5 chromosomes. 7 Here we describe a non-recurrent triplication of 650.4 kb, for which the breakpoint junctions do not involve LCRs (Figure 3b), implicating an alternate underlying mechanism of formation. Its molecular characterization enabled us to experimentally classify it as type II or DUP-TRP/INV-DUP, likely generated by a replication-based mechanism.…”

“…Although deletions of CHRNA7 cause ID and neuropsychiatric phenotypes with relatively high penetrance, 3,4,6 the pathogenicity of CHRNA7 duplications remains unclear, given its high prevalence in the general population with multiple individuals that are clinically unaffected. 7 Therefore, it has been uncertain whether CHRNA7 is a dosage-sensitive gene with penetrant clinical phenotypes for both deletions and duplications. In this report, the family members harboring the triplication are affected with cognitive abilities in the borderline intellectual functioning range, and various degrees of neuropsychiatric pathology.…”

“…This was followed by the description of 55 cases of smaller-sized CHRNA7 duplications (350-680 kb in size). 7 The latter report provided clinical data and pedigree analysis of 11 families and suggested that the duplication may be associated with DD, ID, and a variety of neuropsychiatric phenotypes, but with high variability in expressivity and reduced penetrance. Additional studies showed that 15q13.3 duplications were not associated with schizophrenia, 5 but significantly associated with DD and ID.…”

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

“…By now, several studies have demonstrated that genetic variants in CHRNA7 were associated with various human diseases and traits, such as the associations between CNVs in CHRNA7 and various neurological disorders. [35][36][37][38] In addition, one study conducted in African and European Americans showed that one SNP of CHRNA7 was associated with nicotine dependence, 27 suggesting that the SNPs of CHRNA7 might show association with smoking-related diseases. Yet, till now, no published studies including genome-wide association studies (GWASs) have reported a significant association between CHRNA7 SNPs and the risk of smoking-related diseases, and this Figure 2 Path model for mediating effect of COPD on association between the CNV-3956 and lung cancer risk.…”