379: Long reads reveal hidden structural and repeat variation in autism

Mortazavi M et al., Cell Genomics - PaperCast Base by Base discusses a long-read whole-genome sequencing study of 267 individuals from 63 families that increased detection of structural variants and tandem repeats, resolved complex rearrangements, linked repeat expansions to methylation at FMR1, and estimated rare-variant contributions to ASD heritability. Key terms: long-read sequencing, structural variants, tandem repeats, autism, methylation. Study Highlights:The authors performed long-read WGS (PacBio HiFi and Oxford Nanopore) on 267 individuals and integrated calls with prior short-read data, increasing detection of gene-disrupting SVs by 33% and TRs by 38%. They discovered novel exonic de novo and somatic-mosaic SVs and characterized a previously undescribed class of nested DUP-DEL complex rearrangements. Joint phasing and methylation analysis identified deletions affecting imprinted genes (e.g., ADNP2) and showed that intermediate FMR1 CGG expansions (35–54 repeats) associate with allele-specific hypermethylation. Burden and heritability analyses indicate rare SVs, TRs, and damaging SNVs together explain a measurable fraction of ASD heritability, though power is limited by sample size. Conclusion:Long-read WGS uncovers substantial previously hidden structural and repeat variation and enables combined phased genetic and methylation analysis to improve functional interpretation in ASD, but larger cohorts and deeper coverage are needed to refine associations and heritability estimates. Music:Enjoy the music based on this article at the end of the episode. Article title:Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism First author:Mortazavi M Journal:Cell Genomics DOI:10.1016/j.xgen.2026.101186 Reference:Mortazavi M., Guevara J., Diaz J., et al., 2026. Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism. Cell Genomics 6, 101186. https://doi.org/10.1016/j.xgen.2026.101186 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/long-read-wgs-autism-structural-repeat-variants QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-27. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited portions describing LR-WGS methodology, SV/TR detection gains, mosaic and de novo SVs (STK33), large balanced rearrangements, nested DUP-DEL SVs, imprinting (ADNP2), FMR1 gray-zone methylation, ASD heritability, and study limitations/future directions.- transcript topics: LR-WGS methods and methylation calling; Structural variants and tandem repeats detection gains; Mosaic and de novo SVs (STK33) and functional impact; Complex DUP-DEL rearrangements; Imprinted genes and ADNP2; FMR1 CGG repeats and methylation, XCI independence QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Cohort: LR-WGS perform...