An Automated Functional Annotation Pipeline That Rapidly Prioritizes Clinically Relevant Genes for Autism Spectrum Disorder

• Published in: International journal of molecular sciences 2020-11, Vol.21 (23), p.9029
• Main Authors: Veatch, Olivia J, Butler, Merlin G, Elsea, Sarah H, Malow, Beth A, Sutcliffe, James S, Moore, Jason H
• Format: Article
• Language: English
• Subjects: Animals; Annotations; Autism; Autism Spectrum Disorder - drug therapy; Autism Spectrum Disorder - genetics; Automation; bioinformatics; Biological activity; Biological effects; Brain; Brain - metabolism; Brain - pathology; Consortia; Copy number; Customization; Drug development; Etiology; Gene expression; Gene Expression Regulation; Gene Regulatory Networks; Genes; Genetic screening; Genomes; Genotype & phenotype; human genetics; Humans; Mammals - genetics; Mice; Molecular Sequence Annotation; Mutation - genetics; Nervous system; Nucleotides; Ontology; Pharmacogenomics; Pharmacology; Phenotype; Phenotypes; Precision medicine; Protein Interaction Mapping; Proteins; Seizures
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21239029

Human genetic studies have implicated more than a hundred genes in Autism Spectrum Disorder (ASD). Understanding how variation in implicated genes influence expression of co-occurring conditions and drug response can inform more effective, personalized approaches for treatment of individuals with ASD. Rapidly translating this information into the clinic requires efficient algorithms to sort through the myriad of genes implicated by rare gene-damaging single nucleotide and copy number variants, and common variation detected in genome-wide association studies (GWAS). To pinpoint genes that are more likely to have clinically relevant variants, we developed a functional annotation pipeline. We defined clinical relevance in this project as any ASD associated gene with evidence indicating a patient may have a complex, co-occurring condition that requires direct intervention (e.g., sleep and gastrointestinal disturbances, attention deficit hyperactivity, anxiety, seizures, depression), or is relevant to drug development and/or approaches to maximizing efficacy and minimizing adverse events (i.e., pharmacogenomics). Starting with a list of all candidate genes implicated in all manifestations of ASD (i.e., idiopathic and syndromic), this pipeline uses databases that represent multiple lines of evidence to identify genes: (1) expressed in the human brain, (2) involved in ASD-relevant biological processes and resulting in analogous phenotypes in mice, (3) whose products are targeted by approved pharmaceutical compounds or possessing pharmacogenetic variation and (4) whose products directly interact with those of genes with variants recommended to be tested for by the American College of Medical Genetics (ACMG). Compared with 1000 gene sets, each with a random selection of human protein coding genes, more genes in the ASD set were annotated for each category evaluated ( ≤ 1.99 × 10 ). Of the 956 ASD-implicated genes in the full set, 18 were flagged based on evidence in all categories. Fewer genes from randomly drawn sets were annotated in all categories (x = 8.02, sd = 2.56, = 7.75 × 10 ). Notably, none of the prioritized genes are represented among the 59 genes compiled by the ACMG, and 78% had a pathogenic or likely pathogenic variant in ClinVar. Results from this work should rapidly prioritize potentially actionable results from genetic studies and, in turn, inform future work toward clinical decision support for personalized care based on genetic testing.