SD is a psychiatric disorder with the highest heritability, representing a high concordance rate (60-90%) between monozygotic twins and numerous susceptibility genes.
Population-based studies have estimated the heritability of ASD at 80% or higher. The past few decades have been marked by tremendous progress in the field of ASD genetics, with the identification of numerous genes and copy number variations (CNVs) by microarray and whole-exome sequencing studies. It is estimated that there could be more than 1,000 genes, with no single gene responsible for more than 1-2% of cases.
The genetic susceptibility to ASD is highly heterogeneous, with diverse combinations of low-risk alleles and rare deleterious variants (found at a lower rate in this population). The inheritance of autism spectrum disorder (ASD) is associated with both common and rare inherited variations, resulting in small and large effects, respectively.
The identification of rare de novo mutations that interfere with protein function has advanced significantly over the years. De novo variants can be classified as missense mutations, an acquired modification in which a change in a single nucleotide results in a different amino acid configuration, or as nonsense mutations, in which a change in a single nucleotide generates a stop codon that results in the production of a truncated protein.
In addition to these modifications, genetic haploinsufficiencies of certain genes, such as CACNA1A, SHANK3, and SCN2A, have been linked to ASD. In this scenario, only one of the alleles is functional, resulting in an insufficient protein dosage to ensure normal cellular function. The largest genetic epidemiology study targeting autism spectrum disorder analyzed the exomes of 11,986 patients with the disorder and revealed that mutations in the SCN2A, SYGAP1, and CHD8 genes are most strongly associated with the development of autism spectrum disorder, but many other genes are also strongly associated with autism.
