Exome sequencing and copy number variant (CNV) analyses have contributed significantly to our understanding of the genetic etiology of autism spectrum disorder (ASD). In particular, de novo and private likely-gene-disruptive (LGD) mutations are major risk factors, contributing to 30 percent and 7 percent of simplex autism, respectively. Despite these successes, roughly 60 percent of the genetic etiology of ASD remains unexplained.

Despite the existence of a core set of features and affected biological networks, autism spectrum disorders (ASDs) are genetically heterogeneous. While variants in hundreds of genes have been implicated as causal or risk-conferring for ASD, a large percentage of the heritability of ASDs remains unaccounted for. This suggests that a number of inherited causal or risk mutations linked to autism have gone undiagnosed.

Half a century ago, the introduction of karyotyping transformed human genetics and clinical diagnostics by opening access to gross changes in chromosomes, revealing an entire class of previously undetectable genetic lesions. More recently, new technologies have refined our ability to search for genetic variants that cause disease. Yet in autism spectrum disorders (ASDs), a large proportion of genetic contribution still remains unexplained. Classes of chromosomal alterations that can cause loss-of-function mutations, namely balanced and complex structural variation (SVs), and copy number variants (CNVs), below the threshold of microarray —  collectively referred to as cryptic SVs — remain to be fully considered for their potential contribution to ASD.

Human genetic studies have identified hundreds of genes with variants associated with autism. However, the significance of most of these variants is unknown. At least half of the genes are present in all animals and thus can be studied in genetic model organisms that allow rapid, rigorous genetic analysis.

Ivan Iossifov studies the genetics of autism using the large datasets produced with comparative genomic hybridization, whole-exome and whole-genome sequencing of the extensively phenotyped Simons Simplex Collection.

Although mutations — the fundamental process by which genomic variation is acquired — are necessary to the evolution and success of a species, they are also the origin of all genetic disease. Hence, defining the mechanisms that control their occurrence is crucial to our basic understanding of genome biology, disease mechanisms and, ultimately, evolution.

Autism is diagnosed in boys four times more frequently than in girls. Recent genetic research suggests that this difference is due to the fact that girls are protected from autism risk factors rather than boys being subjected to additional risk factors. The nature of this ‘female protective effect’ remains unknown.

Brian J. O’Roak’s team at Oregon Health and Science University in Portland has been exploring genetic mutations that are difficult to identify using conventional means, and what role these mutations might play in neurodevelopmental disorders. In a previous study, O’Roak and his colleagues sequenced the protein-coding regions of the genome, or ‘exomes,’ in more than 200 families that have a single child affected with autism.

Biological networks provide a natural framework for integrating the diverse genetic variations associated with complex and multifactorial disorders. The main challenge in the analysis of rare genetic variations, such as de novo single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) — duplications or deletions of stretches of DNA — is precisely their rarity. With currently available sample sizes, a vast majority of the observed genetic events are either unique or show only limited recurrency.