Findings demonstrate the need for a wide range of research participants across the autism spectrum to identify a full set of autism genes

In a series of papers published in the journal Nature Genetics, researchers used data from the SPARK (Simons Powering Autism Exploration) research cohort, which was created to advance our understanding of the complex genetics of autism and includes genetic data from nearly 43 000 people with autism. results show differences in genetic influences between people across the autism spectrum.

“Autism is a spectrum and includes people with profound autism who often have cognitive differences and/or epilepsy, as well as talented and exceptional people, often in specific fields. We now realize that genetic contributions to different phenotypes vary in terms of the genes involved when those genes are activated during brain development and the frequency of certain genetic variants in the population,” said Wendy Chung, MD, Ph.D. Principal Investigator of SPARK.

A study, “The integration of de novo and hereditary variants in 35 607 autism case identifies mutations in new genes to effect moderate”, was published in Mother Nature Genetics on 19 August

. The researchers analyzed the DNA of nearly 42 18 people with autism, including 31 members of the SPARK Autism Research Study, as part of SPARK’s ongoing efforts to understand the full spectrum of autism genetics. This largest-ever autism cohort has allowed researchers to identify a group of new “moderate effect” genes that tend to contribute to autism through inherited variants.

Autism is widely known to be inherited, but previous studies have primarily identified autism genes with de novo variants (DNV) – variants that occur spontaneously in germ cells before conception – which are not hereditary. Most of these variants are also implicated in other neurodevelopmental disorders (NDD). Most of the genetic variants of this spell associated with autism have profound effects on the brains of these individuals when they occur. However, only 19% of people with autism have this type of genetic variant.

“For many years we have known from twin studies that there must be inherited genetic variants that lead to autism, but we don’t ‘We have not been able to systematically identify individual genes so far,’ said lead author Pamela Feliciano, Ph.D. SPARK. scientific director. “We have now identified a cluster of genes associated with autism, which may include inherited variants, which begin to explain a different part of the autism spectrum.”

To better understand the full spectrum of autism genes, researchers analyzed 19 843 participants with autism, as well as one or both of their biological parents, and found that approximately 22 % of people with autism had de novo genetic variants that affect function. of the associated gene. Almost 70% of this genetic contribution can be attributed to known autism genes or disorders neurodevelopmental. However, this means that although known genes associated with autism are responsible for the majority of de novo variants, there are still others to be identified.

Researchers have then added 19 764 autistic people and 100 000 non-autistic people from the general population. In this meta-analysis, they identified 42 autism genes whose contribution to Autism is largely due to rare inherited loss-of-function (LOF) variants inherited from parents who do not have cognitive differences or autism. Of these genes, five have never been implicated in neurodevelopmental conditions.

People autistic people who carry inherited variants of these “moderate effect” genes are less likely to have cognitive differences than autistic people who carry LOF variants in well-established autistic genes, such as CHD8 and SCN2A.

“The majority of parents who passed on these genetic variants in our study do not have cognitive differences or autism, but we do know that these genes are associated with autism because we we find that these variants are more frequently inherited by children with autism. We hypothesized that people with autism who have these inherited genetic variants are not as likely to have seizures and cognitive differences as people with de novo genetic variants. this hypothesis,” said Dr. Feliciano.

The scope of the SPARK cohort

A second study also published in Mother nature Genetics, “Rare coding variation provides insight into genetic architecture and of the phenotypic context of autism”, led by a team of researchers supported by the Simons Basis Autism Investigation Initiative (SFARI) and the Autism Sequencing Consortium (ASC ), performed analyzes on the genetic data of 20 373 autistic people, with new genetic data derived mainly from SPARK. The team developed new methods to discover DNA gains and losses, or copy number variants (CNVs), from exome sequencing, and methods to integrate data from these CNVs with learned other rare and de novo inherited variants, and identified 42 genes associated with autism. Most of the evidence came from de novo variants, with smaller but significant contributions from rare inherited variants. The researchers then combined data from autism studies with a large dataset of 22 families in which the child has been diagnosed with developmental delay and/or other neurodevelopmental conditions. These analyzes uncovered 100 genes associated with these various neurodevelopmental outcomes and allowed the team to identify genes more associated with autism than to other neurodevelopmental ailments, and vice versa. They found that genes associated primarily with developmental delay tend to play a crucial role in early neuronal development, while autism genes tend to play a role in more mature neurons.

The study’s lead author, Michael Talkowski, Ph.D. director of the Middle for Genomic Medication at Massachusetts Standard Hospital and member of the Wide Institute, noted that data from SPARK, ASC, and other sources—as well as newly developed methods—allowed us to explore the relative contribution of various genetic variant lessons that contribute to a continuum of neurodevelopmental variability across these sets of data These analyzes suggest that most of the identified genes play a very early role in brain development, although genes with higher mutation rates in autism showed enrichment slightly higher in more mature excitatory neurons There are so many new genes and knowledge about neurodevelopment to pursue from these discoveries, and all of these discoveries have only been possible because of the accessibility of data richness that SPARK and other studies provide for the field.”

Finally, two other studies (Antaki et al, 2022, Warrier et al, 2022) published in a recent issue of Character Genetics analyzed SPARK datasets. These two studies used ASC and SPARK whole genomes, exomes, and single nucleotide polymorphism (SNP) genotypes to determine the contributions of several genetic factors to ASD, including de novo mutations, rare inherited variants, polygenic variants common and sex. The study by Antaki et al. found that different forms of genetic contributors are associated with different symptoms of ASD, and that the wide variety of clinical presentations of individuals across the autism spectrum can be explained by the combinations of genetic factors they carry. Antaki also discovered that genetic contributors to ASD influence the behavior of all family members, including parents and developing siblings.

Jonathan Sebat, Ph.D. professor of psychiatry and cellular and molecular medicine at UCSD and senior author of Antaki et al, a stated, “The spectrum of symptom severity in ASD is attributable to a spectrum of genetic influence. People who meet the diagnostic criteria for autism may have the most genetic factors for autism, but these sorts of factors are present in varying degrees in each of us. We are all somewhere on a continuum.

Together, the four articles or blog posts provide new insights into the genetic basis of autism, a field so varied in its characteristics that it has been difficult to understand its neurobiological basis. Although researchers have yet to identify a more complete picture of the brain molecules and pathways that underlie autism, these new studies will pave the way to a better understanding of this complicated and common condition.


SPARK (Simons Powering Autism Exploration), the largest autism research study in the world, has mobilized nearly 300 contributors, including more than 100 000 autistic people, to participate directly in scientific research, with more than 150 18 their family members also registered as members. The SPARK community brings together people with autism and the world’s leading autism researchers to conduct research that uncovers the genetic implications of autism and informs the development of targeted treatments and support. SPARK’s ultimate goal is to fuel research to help people with autism live their full lives.


SFARI is a project supported by the Simons Basis Autism Investigate Initiative. SFARI’s mission is to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance.

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