Detection of long repeat expansions from PCR-free whole-genome sequence data

Area of Science:

• Genomics
• Bioinformatics
• Human Genetics

Background:

• Short tandem repeat (STR) expansions are challenging to detect with short-read whole-genome sequencing (WGS).
• Accurate identification of these expansions is crucial for diagnosing genetic disorders and advancing precision medicine.

Purpose of the Study:

• To develop and validate a software tool, ExpansionHunter, for accurately genotyping large STR expansions using PCR-free WGS data.
• To assess the performance of ExpansionHunter in detecting pathogenic repeat expansions associated with neurological disorders.

Main Methods:

• Development of the ExpansionHunter software tool.
• Application of ExpansionHunter to PCR-free WGS data from 3001 amyotrophic lateral sclerosis (ALS) patients.
• Validation against repeat-primed PCR (RP-PCR) gold standard data for the C9orf72 expansion.
• Testing on a separate cohort of 152 samples with known pathogenic repeat expansions.

Main Results:

• ExpansionHunter correctly identified all 212 expanded samples for the C9orf72 expansion in ALS patients.
• The tool achieved 99.9% accuracy in classifying wild-type samples.
• ExpansionHunter successfully detected 151 out of 152 known pathogenic repeat expansions in a diverse sample set.

Conclusions:

• ExpansionHunter provides a robust and accurate method for detecting large STR expansions from WGS data.
• This tool facilitates the integration of WGS into clinical diagnostics for repeat expansion disorders.
• ExpansionHunter can be utilized for both the accurate detection of known pathogenic expansions and the discovery of novel ones.