Pangenome discovery of missing autism variants

Area of Science:

• Genomics
• Neurodevelopmental Disorders
• Genetics

Background:

• Autism spectrum disorders (ASDs) exhibit significant genetic and phenotypic heterogeneity, with many cases remaining genetically unexplained.
• Understanding large-effect pathogenic variations is crucial for diagnosing and understanding ASDs.

Purpose of the Study:

• To leverage long-read sequencing for comprehensive genome assembly in families with unsolved autism cases.
• To characterize de novo mutations (DNMs), structural variants (SVs), and DNA methylation profiles.
• To identify novel pathogenic variants contributing to autism etiology.

Main Methods:

• Generated long-read sequencing data for 189 individuals from 51 families.
• Constructed phased and near-complete genome assemblies.
• Applied read- and assembly-based strategies for variant detection, including SVs and DNMs.
• Integrated autism risk genes and regulatory elements for variant prioritization.

Main Results:

• Identified three pathogenic variants in TBL1XR1, MECP2, and SYNGAP1.
• Discovered nine candidate de novo and biparental homozygous SVs, many missed by short-read sequencing.
• Found no increased autosomal SV burden but a trend for increased X chromosome SV burden in affected females.

Conclusions:

• Phased genomes are powerful for discovering complex pathogenic mutations in autism.
• Pangenome analysis efficiently filters common SVs, focusing clinical evaluation on rare variants.
• This approach enhances the identification of genetic causes for unresolved autism cases.