An integrated analysis of rare CNV and exome variation in Autism Spectrum Disorder using the Infinium PsychArray

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a complex and heterogeneous genetic etiology. While a proportion of ASD risk is attributable to common variants, rare copynumber variants (cnVs) and protein-disrupting single-nucleotide variants (SnVs) have been shown to significantly contribute to ASD etiology. We analyzed a homogeneous cohort of 127 ASD Italian families genotyped with the illumina psychArray, to perform an integrated analysis of cnVs and SnVs and to assess their contribution to ASD risk. We observed a higher burden of rare cnVs, especially deletions, in ASD individuals versus unaffected controls. Furthermore, we identified a significant enrichment of rare cnVs intersecting ASD candidate genes reported in the SfARi database. family-based analysis of rare SnVs genotyped by the psychArray also indicated an increased transmission of rare SnV variants from heterozygous parents to probands, supporting a multigenic model of ASD risk with significant contributions of both variant types. Moreover, our study reinforced the evidence for a significant role of VPS13B, WWOX, CNTNAP2, RBFOX1, MACROD2, APBA2, PARK2, GPHN, and RNF113A genes in ASD susceptibility. finally, we showed that the psychArray, besides providing useful genotyping data in psychiatric disorders, is a valuable and cost-efficient tool for genic CNV detection, down to 10 kb. Autism spectrum disorders (ASDs) are a heterogeneous group of neuropsychiatric conditions characterized by impairments in social communication, as well as the presence of restricted interests, stereotyped and repetitive behaviors. ASDs have a worldwide prevalence of about 1%, with males about four times more likely to be affected than females 1. ASDs are highly heterogeneous, both in clinical presentation and with reference to the complex risk architecture. ASD individuals often display other psychiatric and medical conditions including intellectual disability (ID), epilepsy, sleep disorders, motor deficits (hypotonia, apraxia or motor delay), attention-deficit hyperactivity disorder (ADHD), and gastrointestinal disturbances. Undoubtedly, genetic factors play a substantial role in ASD risk. With the availability of microarray and massively parallel sequencing platforms, significant progresses have been made in the last decade in elucidating the underlying genetic risk factors. There is a rising awareness that both common and rare variants contribute to ASD risk. Despite the accumulating evidence supporting a major role of common genetic variation in ASDs 2 , the relative risk conferred by each common variant is very low, thus the identification of common risk variants robustly associated to ASD requires very large sample sizes, which are just starting to be attainable thanks to massive international efforts. A recent genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls first reported common risk variants reaching genome-wide significance 3. Given the difficulties in the identification of common risk alleles, most of our current...

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

“…ASD refers to a broad range of highly complex and heterogeneous neuropsychiatric conditions characterized by challenges with social skills, difficulty in communication and interaction with others, restricted interests, and repetitive behaviors. ADS individuals often suffer from other co-occurring conditions such as intellectual disability (ID), epilepsy, sleep disorders, motor deficits, and attention-deficit hyperactivity disorder (ADHD) [ 40 ]. Many of these ASD co-morbidities overlap with clinical features displayed by individuals affected with the above described WWOX related CNS disorders.…”

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective

“…In addition to the fact that only sometimes the so-called common sequence variants (meaning that the minor allele frequency [MAF] is greater than 5% in the population) or their combinations are implied in the development of ASD, more important for the pathogenesis of ASD are rare (MAF < 1%) or very rare (MAF < 0.1%) single nucleotide variants (SNVs), as well as rare variations in the number of copies (copy number variation, CNV), especially deletions, but also duplications [ 148 , 149 , 150 , 151 , 152 ]. As of April 20, 2020, the Simons Foundation Autism Research Initiative (SFARI), the largest international database for ASD researchers, had a total of 835 genes whose changes or variants are associated with ASD ( ).…”

inCNV: An Integrated Analysis Tool for Copy Number Variation on Whole Exome Sequencing

“…For example, inCNV can be used to find de novo CNVs of a sample within the same family. 4 , 35 To this end, users can filter out common or known CNVs and explore whether the remaining CNVs of the proband are different from their parents. Moreover, we can use inCNV to determine whether the sample has potential to develop a specific disease by the following steps: (1) Integrate the CNVs of the sample of interest with the CNVs of a sample set of the same disease; (2) Search for genes that are specifically related to the disease; (3) Search for the sample of interest; (4) Sort the results by the number of overlapping samples.…”

“…In particular, the study of CNV on whole-exome sequencing (WES) is much more popular 1 and affordable 2 than the study on whole-genome sequencing (WGS). The study of CNVs on WES provides insights into human genome diversity and predisposition to diseases, 3 such as autism, 4 schizophrenia, 5 type-2 diabetes, 6 congenital heart disease (CHD), 7 non-syndromic hearing loss 8 , 9 and inherited retinal degenerations, 10 among others. Nevertheless, issues with the accuracy and complexity of captured CNVs as well as their interpretation still exist.…”