Genetic contributions to autism spectrum disorder

Abstract

Autism spectrum disorder (autism) is a heterogeneous group of neurodevelopmental conditions characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests. This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings. The clinical heterogeneity of autism is mirrored by a complex genetic architecture involving several types of common and rare variants, ranging from point mutations to large copy number variants, and either inherited or spontaneous (de novo). More than 100 risk genes have been implicated by rare, often de novo, potentially damaging mutations in highly constrained genes. These account for substantial individual risk but a small proportion of the population risk. In contrast, most of the genetic risk is attributable to common inherited variants acting en masse, each individually with small effects. Studies have identified a handful of robustly associated common variants. Different risk genes converge on the same mechanisms, such as gene regulation and synaptic connectivity. These mechanisms are also implicated by genes that are epigenetically and transcriptionally dysregulated in autism. Major challenges to understanding the biological mechanisms include substantial phenotypic heterogeneity, large locus heterogeneity, variable penetrance, and widespread pleiotropy. Considerable increases in sample sizes are needed to better understand the hundreds or thousands of common and rare genetic variants involved. Future research should integrate common and rare variant research, multi-omics data including genomics, epigenomics, and transcriptomics, and refined phenotype assessment with multidimensional and longitudinal measures.

Molecular Dysregulation in Autism Spectrum Disorder

“…But many of the candidate gene and linkage investigations are fraught with small sample size contributing to low statistical power and fail to replicate findings. A number of studies have reviewed the linkage and candidate gene studies [ 12 , 27 , 28 ]. Candidate genes which have been the focus of ASD are: CACNAIC , GABAA receptor subunit , FOXP2 , HOXA1 , HOXB1 , HTR2A , MTHFR , RELN , RAY1/ST7 , IMMP2L , SLC6A4 , OXTR , UBE3A and WNT-2 [ 26 , 27 , 28 , 29 , 30 , 31 ].…”

“…A number of studies have reviewed the linkage and candidate gene studies [ 12 , 27 , 28 ]. Candidate genes which have been the focus of ASD are: CACNAIC , GABAA receptor subunit , FOXP2 , HOXA1 , HOXB1 , HTR2A , MTHFR , RELN , RAY1/ST7 , IMMP2L , SLC6A4 , OXTR , UBE3A and WNT-2 [ 26 , 27 , 28 , 29 , 30 , 31 ]. More recently, a role for de novo deleterious NCKAP1 variants was reported in neurodevelopmental delay/autism, as variants can affect the neuronal migration in early cortical development [ 32 ].…”

Mitochondrial Fatty Acid β-Oxidation and Resveratrol Effect in Fibroblasts from Patients with Autism Spectrum Disorder

“…ASD biology is particularly complex, including individual genetic contributions interacting with multiple environmental factors. Genetic risk points to a complex inheritance, with additive contributions from common variants or through rare variants with larger effect sizes [3]. The vast majority of ASD is idiopathic, with a specific cause identified in only 4-20% of patients, including a genetic etiology.…”

“…The vast majority of ASD is idiopathic, with a specific cause identified in only 4-20% of patients, including a genetic etiology. Association of ASD behavioral phenotypes to specific genetic subtypes is envisaged; however, patients with molecularly defined ASD are not easily clinically identified because clinical and neurobehavioral correlates of a given genetic contribution vary widely [3,4].…”

Rare variants in the outcome of social skills group training for autism

“…The molecular genetic understanding of autism spectrum disorder (ASD) has undergone breakthroughs in research settings over the last decade, and these findings are continuously translated into clinical use [1,2]. Currently, the main implication of clinical genetic testing for an individual with ASD is to potentially identify a molecular diagnosis that can be used as a diagnosis specifier according to the Diagnostic & Statistical Manual of Mental Disorders (DSM-5) [3].…”