Long-read genome sequencing uncovers new autism gene variants –

Graphical abstract. Credit: Cell Genomics (2026). DOI: 10.1016/j.xgen.2026.101186

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.

Long-read sequencing reveals hidden variants

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,” said senior author Jonathan Sebat, professor of psychiatry and cellular and molecular medicine at the UC San Diego School of Medicine. “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.”

The work is published in the journal Cell Genomics.

This diagram shows the degree of DNA methylation in the region around the FMR1 gene in two individuals, with red indicating methylated areas. The FMR1 gene is known to cause intellectual disability and autism. Patterns of DNA methylation, which regulates the activity of genes, could explain how this and other genes contribute to autism spectrum disorder. Credit: UC San Diego Health Sciences

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.

What the findings could mean next

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.