RESEARCH ARTICLE Analysis of CHRNA7 Rare Variants in Autism Spectrum Disorder Susceptibility Elena Bacchelli, 1 Agatino Battaglia, 2 Cinzia Cameli, 1 Silvia Lomartire, 1 Raffaella Tancredi, 2 Susanne Thomson, 3 James S Sutcliffe, 3 and Elena Maestrini 1 * 1 Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy 2 Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Calambrone (Pisa), Italy 3 Department of Molecular Physiology & Biophysics and Psychiatry and Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee Manuscript Received: 16 May 2014; Manuscript Accepted: 30 September 2014 Chromosome 15q13.3 recurrent microdeletions are causally associated with a wide range of phenotypes, including autism spectrum disorder (ASD), seizures, intellectual disability, and other psychiatric conditions. Whether the reciprocal microdu- plication is pathogenic is less certain. CHRNA7, encoding for the alpha7 subunit of the neuronal nicotinic acetylcholine receptor, is considered the likely culprit gene in mediating neurological phenotypes in 15q13.3 deletion cases. To assess if CHRNA7 rare variants confer risk to ASD, we performed copy number variant analysis and Sanger sequencing of the CHRNA7 coding sequence in a sample of 135 ASD cases. Sequence variation in this gene remains largely unexplored, given the existence of a fusion gene, CHRFAM7A, which includes a nearly identical partial duplication of CHRNA7. Hence, attempts to sequence coding exons must distinguish between CHRNA7 and CHRFAM7A, making next-generation sequencing approaches unreliable for this purpose. A CHRNA7 microduplication was detected in a patient with autism and moderate cognitive impairment; while no rare damaging variants were identified in the coding region, we detected rare variants in the promoter region, previously described to functionally reduce transcription. This study rep- resents the first sequence variant analysis of CHRNA7 in a sample of idiopathic autism. Ó 2015 Wiley Periodicals, Inc. Key words: 15q13.3; neurodevelopmental disorders; copy number variants; sequence variants INTRODUCTION Autism spectrum disorder (ASD) comprises a group of neuro- developmental traits characterized by repetitive and stereotypic behaviors and impairments in communication and social inter- actions, with an onset within the first three years of age. Family studies indicate a significant genetic basis for ASD susceptibility, but the underlying genetic architecture is highly complex and heterogeneous. Recent genome-wide studies have documented that common variants exert only small individual main effects on risk, although when common variation (CV) across the genome is considered in aggregate, CV is found to contribute measurably to ASD risk [Klei et al., 2012]. In addition, rare inherited and de novo copy number variants (CNVs) and single nucleotide variants (SNVs) of large effect size have a major role in the etiology of ASD, contributing in as many as 5–10% of idiopathic cases exam- ined [Devlin and Scherer, 2012]. In spite of the overall relevance of CNVs in autism, each individual risk CNVs is very rare. Recurrent CNVs, still infre- quent or rare, are typically flanked by segmental duplications and are often implicated in multiple developmental and/or neuro- logical disorders, perhaps not surprisingly given the overlap in phenotype across conditions. Among recurrent CNVs, the 15q13.3 microdeletion is highly but not always fully penetrant, and it is significantly enriched in cases of intellectual disability, autism, epilepsy, schizophrenia, and bipolar disorder [Sharp et al., 2008; Stefansson et al., 2008; Ben-Shachar et al., 2009 Dibbens et al., 2009; Helbig et al., 2009; Miller et al., 2009; Pagnamenta et al., 2009; van Bon et al., 2009; Cooper et al., 2011]. This 15q13.3 recurrent microdeletion, resulting in the loss of a 1.5 Mb region between low-copy repeat (LCR) sequences How to Cite this Article: Bacchelli E, Battaglia A, Cameli C, Lomartire S, Tancredi R, Thomson S, Sutcliffe JS, Maestrini E. 2015. Analysis of CHRNA7 rare variants in Autism spectrum disorder susceptibility. Am J Med Genet Part A 9999:1–9. Conflict of interest: The authors declare no conflict of interest.  Correspondence: Elena Maestrini, Dept. of Pharmacy and Biotechnology, University of Bologna, via Selmi 3, Bologna 40126, Italy. E-mail: elena.maestrini@unibo.it Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2015 DOI 10.1002/ajmg.a.36847 Ó 2015 Wiley Periodicals, Inc. 1