Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients

Background: Autism spectrum disorder (ASD) is genetically and phenotypically heterogeneous. Former genetic studies suggested that both common and rare genetic variants play a role in the etiology. In this study, we aimed to analyze rare variants detected by next generation sequencing (NGS) in an autism cohort from Hungary.

Methods: We investigated the yield of NGS panel sequencing of an unselected ASD cohort (N = 174 ) for the detection of ASD associated syndromes. Besides, we analyzed rare variants in a common disease-rare variant framework and performed rare variant burden analysis and gene enrichment analysis in phenotype based clusters.

Results: We have diagnosed 13 molecularly proven syndromic autism cases. Strongest indicators of syndromic autism were intellectual disability, epilepsy or other neurological plus symptoms. Rare variant analysis on a cohort level confirmed the association of five genes with autism (AUTS2, NHS, NSD1, SLC9A9, and VPS13). We found no correlation between rare variant burden and number of minor malformation or autism severity. We identified four phenotypic clusters, but no specific gene was enriched in a given cluster.

Conclusion: Our study indicates that NGS panel gene sequencing can be useful, where the clinical picture suggests a clinically defined syndromic autism. In this group, targeted panel sequencing may provide reasonable diagnostic yield. Unselected NGS panel screening in the clinic remains controversial, because of uncertain utility, and difficulties of the variant interpretation. However, the detected rare variants may still significantly influence autism risk and subphenotypes in a polygenic model, but to detect the effects of these variants larger cohorts are needed.