Analysis of CHRNA7 Rare Variants in Autism Spectrum Disorder Susceptibility

作者：Bacchelli Elena; Battaglia Agatino; Cameli Cinzia; Lomartire Silvia; Tancredi Raffaella; Thomson Susanne; Sutcliffe James S; Maestrini Elena^*

来源：American Journal of Medical Genetics, Part A, 2015, 167(4): 715-723.

DOI：10.1002/ajmg.a.36847

• 15q13.3
• neurodevelopmental disorders
• copy number variants
• sequence variants

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 microduplication 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 represents the first sequence variant analysis of CHRNA7 in a sample of idiopathic autism.

• 出版日期2015-4