Autism is a neurodevelopmental disorder with an estimated prevalence of 1 in 150 children which makes it more common than childhood cancer and juvenile diabetes. It is estimated that there are more than 100,000 individuals affected by autism in Canada and tens of millions worldwide. It is well established that genetic factors play important role in the pathophysiology of autism; still, our current understanding of these genetic factors is limited and cause of autism remains an important question. During the past decade, after completion of human genome, several new high throughput genome scan technologies have been developed such as microarrays. In the present study, we undertook the challenge of identifying X-chromosomal genes involved in autism by performing genome-wide copy number variation analysis of more than 400 probands with autism using Affymetrix 500K single nucleotide polymorphism (SNP) microarrays. We identified copy number variants implicating several genes on the chromosome X such as PTCHD1, IL1RAPL1, IL1RAPL2 and TSPAN7 as autism candidate genes. We also demonstrated that autism and intellectual disability may share some of these genes as etiologic factors. We performed a comprehensive analysis of PTCHD1 locus and showed that mutations at this locus are associated with autism in ~1 % of the cases. This study also demonstrated that PTCHD1 mutations can cause intellectually disability with or without autism, and that the PTCHD1 protein may act as a receptor in Hedgehog signaling pathway. We have also carried out a detailed analysis of TSPAN7 and IL1RAPL1 to explore the contributions of these genes in autism. We identified one family with intronic deletion of IL1RAPL1 and another case with a missense mutation in this gene, thus implicating this known intellectual disability gene in autism. Our findings highlight the importance of the X chromosome in the etiology of autism, and demonstrate the power of copy number variation analysis coupled with other technologies in identification of disease genes, in particular for complex genetic disorders such as autism.

Autism is a neurodevelopmental disorder with an estimated prevalence of 1 in 150 children which makes it more common than childhood cancer and juvenile diabetes. It is estimated that there are more than 100,000 individuals affected by autism in Canada and tens of millions worldwide. It is well established that genetic factors play important role in the pathophysiology of autism; still, our current understanding of these genetic factors is limited and cause of autism remains an important question. During the past decade, after completion of human genome, several new high throughput genome scan technologies have been developed such as microarrays. In the present study, we undertook the challenge of identifying X-chromosomal genes involved in autism by performing genome-wide copy number variation analysis of more than 400 probands with autism using Affymetrix 500K single nucleotide polymorphism (SNP) microarrays. We identified copy number variants implicating several genes on the chromosome X such as PTCHD1, IL1RAPL1, IL1RAPL2 and TSPAN7 as autism candidate genes. We also demonstrated that autism and intellectual disability may share some of these genes as etiologic factors. We performed a comprehensive analysis of PTCHD1 locus and showed that mutations at this locus are associated with autism in ~1 % of the cases. This study also demonstrated that PTCHD1 mutations can cause intellectually disability with or without autism, and that the PTCHD1 protein may act as a receptor in Hedgehog signaling pathway. We have also carried out a detailed analysis of TSPAN7 and IL1RAPL1 to explore the contributions of these genes in autism. We identified one family with intronic deletion of IL1RAPL1 and another case with a missense mutation in this gene, thus implicating this known intellectual disability gene in autism. Our findings highlight the importance of the X chromosome in the etiology of autism, and demonstrate the power of copy number variation analysis coupled with other technologies in identification of disease genes, in particular for complex genetic disorders such as autism.