Researchers at the University of California San Diego have identified new genetic variants associated with autism spectrum disorder (ASD) by using long-read whole genome sequencing (LR-WGS), an emerging approach that reads large sections of the genome at once, making it easier for scientists to find new genetic variants and understand how genetic variants affect the function of a gene. The team found that compared to traditional short-read approaches, LR-WGS enhanced the discovery of several categories of genetic variants. The findings may pave the way for more accurate genetic tests and could enable new therapies targeting specific genetic mechanisms underlying ASD.

Despite significant progress in understanding the genetics of autism, a substantial portion of its genetic basis remains unexplained. This gap is what researchers call the “missing heritability.” In their latest study, the researchers show that long-read sequencing can discover new gene mutations that were hidden from view when they used more traditional short-read sequencing technologies. This is one of the first studies of autism to utilize this approach at scale.

Long-read technologies are game changers in terms of the diverse functional information we can get from a single genome sequence. This technology can improve our understanding of the genetic basis of autism and other neurodevelopmental disorders, and may ultimately lead to better diagnostics and targeted therapies.”


Jonathan Sebat, senior author, professor of psychiatry and cellular and molecular medicine, UC San Diego School of Medicine

Analyzing 267 genomes from families with autism, the study found:


LR-WGS enhances the discovery of gene-disrupting structural variants (changes in genes) and tandem repeats (repeated sections of DNA) by 33% and 38%, respectively, compared to traditional short-read sequencing.
Some of the new mutations found are complex rearrangements of genes, which can disrupt gene function and contribute to the development of autism.
By analyzing data on genetic variants in tandem with DNA methylation – small chemical modifications that regulate the activity of a gene – the researchers could determine how mutations impact the function of a gene.

The researchers caution that though this study is the largest of its kind to date, even larger studies analyzing more genomes will be required to estimate exactly how much of the missing heritability can now be explained with long reads. Sebat hypothesizes that LR-WGS could double the amount of heritability explained by certain types of variants, such as tandem repeats and structural variants.

For now, the study offers new insights into the genetic origins of autism and highlights the potential of LR-WGS to reveal complex genetic variations and their functional consequences with a single test.

The study was published in Cell Genomics and funded, in part, by grants from the National Institute for Mental Health (MH113715, MH133899), the National Institute of Drug Abuse (U01DA051234), and the National Human Genome Research Institute (1R01HG010149).

Source:

University of California – San Diego

Journal reference:

Mortazavi, M., et al. (2026). Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism. Cell Genomics. DOI: 10.1016/j.xgen.2026.101186. https://www.cell.com/cell-genomics/fulltext/S2666-979X(26)00048-0