Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by differences in social communication and restricted or repetitive behaviors. The genetics of ASD are complex, involving not a single gene, but rather a combination of many genetic variations and, in some cases, entirely new genetic changes. The risk for ASD is distributed across the genome and is influenced by both inherited and non-inherited factors. Understanding this varied genetic architecture is important for grasping how risk is transmitted within a family.
The Complex Genetic Landscape of Autism
The genetic contribution to ASD is considered polygenic, meaning many genes contribute small effects to the overall risk. Scientists categorize these genetic factors into two main types: common variants and rare variants. Common genetic variants are found frequently in the general population, and each one individually has only a slight influence on increasing susceptibility to ASD. The cumulative effect of hundreds or thousands of these common variants, measured by a polygenic risk score, accounts for a substantial portion of the overall inherited risk.
Rare genetic variants are much less common but carry a larger individual influence on the likelihood of developing ASD. These include single-letter changes in the DNA code or larger structural alterations known as Copy Number Variations (CNVs). CNVs involve the deletion or duplication of large segments of DNA, often encompassing multiple genes. Specific CNVs, such as those occurring in the 16p11.2 or 22q11.2 chromosomal regions, are strongly associated with an increased chance of an ASD diagnosis.
This intricate collection of genetic factors means that the risk is spread across the entire genome rather than residing in a single “autism gene.” The interaction between these many common and rare variants determines an individual’s total genetic liability. The presence of a rare, high-influence variant can sometimes be enough to cause ASD, but in many cases, it is the combination of such a variant with an inherited background of common risk variants that leads to the condition.
Parental Roles in Inherited Autism Risk
When focusing on the inherited component of ASD risk, the “female protective effect” offers insight into how genetic variants are passed down. This effect suggests that females have a greater tolerance for genetic risk compared to males, who are diagnosed with ASD at a rate three to four times higher. A female may carry a greater burden of common or rare risk variants without expressing the condition, effectively making her an unaffected carrier.
Studies show that mothers of children with ASD tend to carry more polygenic risk than fathers of affected children. This suggests the genetic threshold for developing ASD is higher in females, requiring a larger total genetic burden for the disorder to manifest. Consequently, a mother can pass on significant risk variants to her child that she herself tolerated without being diagnosed.
The father’s age at conception also influences the overall risk of having a child with ASD, although this is distinct from the inheritance of established risk variants. As men age, the process of sperm production involves continuous cell division. This ongoing division allows for the accumulation of new genetic changes, which are then passed to the offspring. While both parents contribute to the inherited genetic background, the maternal tolerance for risk variants and the paternal accumulation of new mutations are two distinct ways parents influence the genetic liability of their child.
The Role of Spontaneous Genetic Changes
In a substantial number of ASD cases, the genetic change is not inherited from either parent but arises spontaneously; these are called de novo mutations. These “new” mutations occur in the sperm or egg cell of one parent, or very early in the developing embryo, and were not present in the parents’ other cells. They represent a genetic risk that was not carried by either parent in the traditional sense.
De novo mutations are thought to account for approximately 5% to 20% of all ASD cases. They are particularly relevant in families with no prior history of the disorder. These spontaneous changes often target genes involved in the development and functioning of brain cells, such as those regulating neuronal growth and synaptic operation.
The link between advanced paternal age and increased ASD risk is primarily explained by the accumulation of these de novo mutations. As a father ages, the increased number of cell divisions raises the probability of a random copying error in the DNA. Research suggests that for every additional year of paternal age, the child inherits about two more new mutations, which can shift the child’s genetic liability across the threshold for an ASD diagnosis.
Understanding Recurrence Risk and Genetic Counseling
For families who have one child with ASD, understanding the recurrence risk—the probability of having another child with the condition—is a common concern. The risk is significantly higher than in the general population, with recent prospective studies estimating a recurrence rate of approximately 10% to 25% for a second child. This rate can climb higher if a family already has multiple affected children.
The exact recurrence risk is heavily influenced by the genetic cause of the first child’s ASD. If the condition was caused by a de novo mutation, the chance of it recurring is low, though inherited polygenic factors still contribute to risk. Conversely, if the first child inherited a specific rare variant from an unaffected parent, the recurrence risk for future children who inherit the same variant is much higher. Recurrence risk is also higher for siblings of a female with ASD than for siblings of a male with ASD, consistent with the female protective effect.
Genetic counseling provides an opportunity for families to review their specific situation and understand the probability of recurrence. Genetic counselors gather a detailed family history and may recommend genetic testing, such as chromosomal microarray analysis or whole-exome sequencing, for the affected child. Identifying a specific genetic cause, which happens in about 10% to 30% of cases with current sequencing technology, allows for a more personalized and accurate risk assessment for future pregnancies.