Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent differences in social communication and interaction, alongside restricted, repetitive patterns of behavior, interests, or activities. Research confirms the condition has a strong biological basis, with twin studies indicating a high heritability rate ranging between 70% and 90%. This substantial genetic contribution involves chromosomes, which house an individual’s DNA within the cell’s nucleus. The genetic architecture of ASD is highly heterogeneous, meaning no single genetic cause exists, but rather a wide array of variations contribute to the disorder.
Genetic Complexity of Autism
The genetic underpinnings of ASD involve two distinct, often interacting, classes of genetic variation. One major mechanism is polygenic inheritance, where many common gene variants, each having a small effect, combine to create an overall susceptibility. These common variants are inherited from the parents and account for at least 50% of the genetic risk in some populations.
The second mechanism involves rare variants that have a much larger impact on risk. These changes are either inherited from an unaffected parent or arise de novo. A de novo mutation is a genetic change present in the affected child but not in either parent’s germline. These mutations are observed more frequently in families where only one child is affected and may contribute to 52% to 67% of ASD cases in these low-risk families.
Large-Scale Chromosomal Changes
Large-scale changes in chromosome structure are the most significant genetic alterations associated with ASD. These are known as Copy Number Variations (CNVs), involving the duplication (gain) or deletion (loss) of DNA segments. CNVs can span millions of base pairs, encompassing multiple genes and causing a change in gene dosage.
Several specific CNVs are frequently identified in ASD. A microdeletion on chromosome 16 at the 16p11.2 region is found in about 1% of cases. The chromosome 22q11.2 region is also well-known, where both deletions and duplications are associated with neurodevelopmental disorders. For instance, the 22q11.2 deletion is linked to DiGeorge or Velocardiofacial syndrome and is associated with ASD rates ranging from 14% to 50%.
Recurrent CNVs have also been detected on chromosome 15 in the 15q11–q13 region, where both maternal duplications and deletions are implicated. These large structural changes affect genes involved in brain development and function. The size and location of these CNVs determine the specific syndrome and clinical presentation, highlighting the link between chromosomal structure and ASD susceptibility.
Identifying Specific Gene Variations
A separate category of genetic variations involves changes at the molecular level, affecting specific single genes. These variations include small insertions, deletions, or single nucleotide changes. Researchers have identified hundreds of ASD-associated genes, many of which encode proteins that regulate the structure and function of synapses—the junctions that allow neurons to communicate.
The SHANK3 gene is a well-studied example, providing instructions for a scaffolding protein located in the postsynaptic density of excitatory synapses. Mutations in SHANK3 are among the most common single-gene causes of ASD, accounting for about 1% of all cases. These mutations disrupt the organization of the synaptic machinery, which is thought to cause the behaviors seen in ASD.
Another important gene is FMR1, which causes Fragile X Syndrome (FXS), the most common single-gene disorder associated with ASD. The FMR1 gene produces FMRP, an RNA-binding protein that regulates the translation of other proteins essential for synaptic plasticity. A CGG trinucleotide repeat expansion in FMR1 leads to a loss of this protein’s function, and about 50% of males with FXS also meet the diagnostic criteria for ASD.
Implications for Diagnosis and Screening
The discovery of diverse genetic variations has influenced the development of clinical diagnostic tools for ASD. Genetic testing is an important component of the clinical workup, especially for individuals with co-occurring features or intellectual disability. The standard of care often begins with Chromosomal Microarray Analysis (CMA), which detects large-scale Copy Number Variations (CNVs).
Following CMA, Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) can search for smaller, single-gene variations. WES focuses on the exome, the protein-coding regions of the genome, which contain most known disease-related variants. Although CMA is effective for structural changes, WES often demonstrates a higher diagnostic yield, identifying a genetic cause in a significant percentage of patients.
Genetic testing provides families with a precise molecular diagnosis, clarifying the genetic basis of the condition and guiding treatment options. Due to the complexity of ASD genetics, genetic counseling remains a necessary part of the process. Counselors help families understand the results, the risk of recurrence, and the limitations regarding predictive testing when a clear monogenic cause is absent.