A NOVEL PHENOTYPE BATTERY FOR ENHANCING GENETIC DIAGNOSIS OF AUTISM SPECTRUM DISORDER

Background: Autism Spectrum Disorder (ASD) is a genetically and phenotypically heterogeneous condition. Current genetic diagnostic approaches identify clinically relevant variants in fewer than 20% of cases, underscoring the need for improved strategies to detect variants that contribute to ASD susceptibility.
Objective: To develop and evaluate a phenotype-driven approach for prioritizing ASD genetic variants.
Methods: We analyzed comprehensive phenotypic and whole-exome sequencing (WES) data from 115 children enrolled in the Azrieli National Center for Autism and Neurodevelopment Research (ANCAN) database. Phenotypic information was standardized using the Human Phenotype Ontology (HPO) and aggregated into a novel battery of ASD phenotypes. For each individual, gene-disrupting variants identified by WES were prioritized by assessing the concordance between the expected phenotype profile of the gene and the observed phenotypic profile of the carrier.
Results: A total of 226 HPO terms, grouped into 40 broad phenotype categories, were identified. Known ASD genes exhibited significantly higher counts of associated expected phenotypes compared with non-ASD genes (mean ± SD: 16 ± 6.7 vs. 7.3 ± 6.0; p < 2.2e-16), supporting the relevance of the phenotype battery to ASD genetics. Among 20 children with previously confirmed clinically relevant variants, our phenotype-driven approach successfully prioritized 15 as top-ranked candidates, demonstrating its diagnostic utility.
Conclusions: This novel phenotype battery improves the prioritization of ASD-associated genetic variants and has the potential to enhance the diagnostic yield of WES in clinical genetics, offering a promising tool for precision medicine in ASD.