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.
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Acknowledgements
We are indebted to the family who participated in this study. Dr Schaaf’s work is generously supported by the Joan and Stanford Alexander Family. Dr Schaaf is also a recipient of a Doris Duke Clinical Scientist Development Award. NIH grant HD037283 supported Dr Ge’s work in the laboratory of Dr Arthur Beaudet. In addition, this work was supported in part by US National Institute of Neurological Disorders and Stroke grant NS058529 to JRL.
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Drs Carvalho, Lupski, Stankiewicz, Cheung, Bi and Schaaf are faculty members of the Department of Molecular and Human Genetics at Baylor College of Medicine, which derives revenue from the chromosomal microarray analysis offered in the Medical Genetics Laboratory.
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Soler-Alfonso, C., Carvalho, C., Ge, J. et al. CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree. Eur J Hum Genet 22, 1071–1076 (2014). https://doi.org/10.1038/ejhg.2013.302
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DOI: https://doi.org/10.1038/ejhg.2013.302
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