Scientists have spent decades trying to understand why autism affects some children and not others, even when they grow up in the same home. New research led by international teams is bringing the picture into focus. They now propose that autism is shaped mostly by two major genetic forces. This discovery is opening the door to new treatments that may help the people with the most severe forms of the condition.
Much of this work comes from leading geneticists such as Joseph Buxbaum at the Icahn School of Medicine at Mount Sinai, Thomas Bourgeron at the Institut Pasteur, and Christian Schaaf at Heidelberg University. Their groups have built large international collaborations including the Autism Sequencing Consortium and the Genomics of Autism in Latin America project. These teams compare genetic patterns in thousands of families to find the roots of autism.
The Two Main Genetic Drivers
Researchers now describe two forces shaping autism genetics.
The first force is de novo mutations. These are brand new genetic changes that appear in the egg, sperm, or early embryo. They are not inherited from either parent. Although they are rare, a single de novo mutation can have a powerful impact. Children with these mutations often have more serious symptoms, including intellectual disability, low IQ, or the need for lifelong support.
The second force is polygenic variation. This involves hundreds or even thousands of inherited gene variants. Each variant has a tiny effect, but together they can raise the likelihood of autism. Polygenic variation may explain up to fifty percent of all autism cases. These inherited patterns are far more common but much harder to identify, since they depend on how all of a person’s genes interact.
How the Drivers Were Discovered
Decades of twin studies showed that autism has a strong genetic basis. When one identical twin is autistic, the chance the other is autistic can exceed ninety percent. Later, advances in genome and exome sequencing allowed scientists to identify individual mutations. Large studies comparing thousands of autistic children, their parents, and their neurotypical siblings revealed where de novo mutations appear and how inherited variants are passed down.
One of the clearest examples came from a French family with three children who had different numbers of copies of a gene called SHANK3. The typically developing brother had the normal two copies. His older brother with mild autism had an extra piece of chromosome 22 that gave him additional SHANK3 material. Their sister with severe autism had only one working copy because a piece of chromosome 22 was missing. This single gene difference shaped each child’s development in sharp and surprising ways.
More than one hundred genes are strongly linked to autism. Many of them influence how brain cells form, mature, and communicate.
SHANK3 helps create the structures that connect neurons. Too few or too many copies can disrupt the signals that support learning and behavior.
CHD8 controls how DNA is packaged in cells. When CHD8 is mutated, important developmental genes may fail to activate. This can affect how brain cells grow and organize themselves.
Other genes cause indirect effects. For example, children with phenylketonuria cannot break down the amino acid phenylalanine. If they eat foods containing it, the buildup can damage brain development and lead to autism-like symptoms.
Environmental factors can increase the number of de novo mutations. Older parents, smokers, and people exposed to radiation or toxins may accumulate more DNA changes in their eggs or sperm. This may help explain why autism risk rises with parental age.
How the Genes Were Identified
Researchers used whole genome sequencing, exome sequencing, biochemical testing, and large statistical studies across many countries. Global projects such as GALA also showed that the major autism genes are consistent across ancestries. In Latin America, thirty-five genes linked to autism matched many found in European populations. According to the researchers, this indicates that the core biology of autism is largely universal.
Scientists also used behavior-based genetic screens. One example is the Reading the Mind in the Eyes test, developed by Simon Baron-Cohen. The test measures how well a person can detect emotions from photographs of human eyes. By pairing large numbers of test results with DNA samples from more than eighty thousand participants, researchers identified gene variants tied to social recognition and emotion processing.
De novo mutations often push development off course during the formation of the fetal brain, especially between weeks twelve and twenty four of pregnancy. These children may show profound delays that require constant care.
Polygenic variations operate differently. They create a background of subtle tendencies. Some of these variants are linked to weaker social skills, but others are tied to strengths such as higher mathematical ability, advanced spatial reasoning, pattern recognition, and even artistic skill. Only when enough of these inherited variants accumulate do they reach the threshold where autism appears.
How These Discoveries May Guide Treatment
Knowing a child’s specific genetic cause can lead to targeted interventions. Schaaf’s team treated a four year old boy who was losing speech and becoming aggressive. Tests showed a mutation in the TMLHE gene had caused severe carnitine deficiency. By simply supplementing carnitine, his regression stopped and his language and behavior improved.
Gene targeted therapies fall into several categories. Some aim to switch on a healthy copy of a gene when the other is damaged. Others try to boost the activity of the working gene so that it can compensate. Some approaches give supplements or drugs that correct downstream problems when the gene itself cannot be directly fixed.
Researchers are testing these ideas in related conditions such as Angelman syndrome and Fragile X syndrome. Early results show improvements in cognition, language, and daily living skills. In autism, clinical trials are beginning for children with SHANK3 mutations. The FDA recently approved a gene therapy trial in children who also have Phelan McDermid syndrome.
In the future, gene editing tools such as Crispr may allow scientists to intervene even earlier, possibly before birth, to lessen the severity of certain mutations.
Many scientists are hopeful. They believe that identifying the major pathways behind autism could lead to treatments that reduce profound disability. Buxbaum stresses that these therapies are aimed only at people with severe autism who cannot speak, cannot care for themselves, and require constant support. He notes that those with milder forms do not need genetic treatment.
However, some researchers and autistic advocates express concerns. They worry that genetic data could be misused or misunderstood. Some fear that prenatal testing could lead to pressure to eliminate autistic traits before birth. Others argue that the research focuses too heavily on autism rather than intellectual disability, which often overlaps.
Researchers such as Bourgeron emphasize that the goal is not to erase neurodiversity but to help individuals who suffer from serious medical complications. They call for more collaboration with autistic people and their families to ensure that treatments respect both needs and identities.
Genetics explains about sixty percent of autism, but not all of it. Environmental factors and diagnostic changes also play roles. Profound autism has risen sharply over recent decades, suggesting that something beyond genes is contributing.
Even so, the discovery of autism’s two main genetic drivers represents a major step in understanding how the condition arises. The work is still young, but as scientists map the pathways behind autism, new treatments may emerge that can prevent regression, support development, and improve the lives of those who need the most help.
