Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism

Milad Mortazavi; James Guevara; Joshua Diaz; Stephen Tran; Helyaneh Ziaei Jam; Chloe Reeves; Sergey Batalov; Kristen Jepsen; Matthew Bainbridge; Aaron D Besterman; Melissa Gymrek; Abraham A Palmer; Jonathan Sebat

doi:10.1016/j.xgen.2026.101186

Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism

Cell Genom. 2026 May 13;6(5):101186. doi: 10.1016/j.xgen.2026.101186. Epub 2026 Mar 9.

Authors

Affiliations

¹ Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
² Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
³ Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
⁵ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Codified Genomics LLC, Houston, TX 77030, USA.
⁶ Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital San Diego, San Diego, CA 92123, USA; Laura Rodriguez Research Institute, Family Health Centers of San Diego, San Diego, CA 92101, USA.
⁷ Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁸ Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁹ Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine and Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jsebat@ucsd.edu.

Abstract

Long-read whole-genome sequencing (LR-WGS) technologies enhance the discovery of structural variants (SVs) and tandem repeats (TRs). We performed LR-WGS on 267 individuals from 63 autism spectrum disorder (ASD) families and generated an integrated call set combining long- and short-read data. LR-WGS increased detection of gene-disrupting SVs and TRs by 33% and 38%, respectively, and enabled identification of novel exonic de novo germline and somatic SVs. We observed complex SV patterns, including a class of nested duplication-deletion events. By joint analysis of phased genetic variation and DNA methylation, we identified deletions of imprinted genes and demonstrated the effect of intermediate TR expansions (35-54 CGG) on the methylation of FMR1 promoter. Rare SVs, TRs, and damaging SNVs together accounted for 7.4% (95% confidence interval [CI], 2.7%-17%) of the heritability of ASD. These findings demonstrate how LR-WGS can resolve complex genetic variation and its functional consequences and regulatory effects in a single assay.

Keywords: CGG repeat; FMR1; autism; burden test; complex SVs; de novo mutation; long-read sequencing; methylation; structural variation; tandem repeat.

MeSH terms

Autism Spectrum Disorder* / genetics
Autistic Disorder* / genetics
DNA Methylation / genetics
Female
Fragile X Messenger Ribonucleoprotein 1 / genetics
Genetic Variation
Genomic Structural Variation* / genetics
Humans
Male
Promoter Regions, Genetic
Tandem Repeat Sequences* / genetics
Whole Genome Sequencing* / methods

Substances

Fragile X Messenger Ribonucleoprotein 1
FMR1 protein, human