Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data

Abstract

AbstractBackgroundAutism spectrum disorder (ASD) is a heterogenous multifactorial neurodevelopmental condition with a significant genetic susceptibility component. Thus, identifying genetic variations associated with ASD is a complex task. Whole-exome sequencing (WES) is an effective approach for detecting extremely rare protein-coding single-nucleotide variants (SNVs) and short insertions/deletions (INDELs). However, interpreting these variants’ functional and clinical consequences requires integrating multifaceted genomic information.MethodsWe compared the concordance and effectiveness of three bioinformatics tools in detecting ASD candidate variants (SNVs and short INDELs) from WES data of 220 ASD family trios registered in the National Autism Database of Israel. We studied only rare (<1% population frequency) proband-specific variants. According to the American College of Medical Genetics (ACMG) guidelines, the pathogenicity of variants was evaluated by theInterVarandTAPEStools. In addition, likely gene-disrupting (LGD) variants were detected based on an in-house bioinformatics tool,Psi-Variant, that integrates results from seven in-silico prediction tools.ResultsOverall, 605 variants in 499 genes distributed in 193 probands were detected by these tools. The overlap between the tools was 64.1%, 17.0%, and 21.6% forInterVar–TAPES,InterVar–Psi-Variant, andTAPES–Psi-Variant, respectively. The intersection betweenInterVarandPsi-Variant(I∩P) was the most effective approach in detecting variants in known ASD genes (OR = 5.38, 95% C.I. = 3.25–8.53), while the union ofInterVarandPsi-Variant(IUP) achieved the highest diagnostic yield (30.9%).ConclusionsOur results suggest that integrating different variant interpretation approaches in detecting ASD candidate variants from WES data is superior to each approach alone. The inclusion of additional criteria could further improve the detection of ASD candidate variants.