Abstract
Many studies based on chromosomal microarray and next-generation sequencing (NGS) have identified hundreds of genes associated with autism spectrum disorder (ASD) risk, demonstrating that there are several complex genetic factors that contribute to ASD risk. We performed targeted NGS gene panels for 120 selected genes, in a clinical population of 40 children with well-characterized ASD. The variants identified were annotated and filtered, focusing on rare variants with a minimum allele frequency <1% in GnomAD. We found 147 variants in 39 of the 40 patients. It was possible to perform family segregation analysis in 28 of the 40 patients. We found 4 de novo and 101 inherited variants. For the inherited variants, we observed that all the variants identified in the patients came equally from the paternal and maternal genetic makeup. We identified 9 genes that are more frequently mutated than the others, and upon comparing the mutational frequency of these 9 genes in our cohort and the mutational frequency in the GnomAD population, we found significantly increased frequencies of rare variants in our study population. This study supports the hypothesis that ASD is the result of a combination of rare deleterious variants (low contribution) and many low-risk alleles (genetic background), highlighting the importance of MET and SLIT3 and the potentially stronger involvement of FAT1 and VPS13B in ASD. Taken together, our findings reinforce the importance of using gene panels to understand the contribution of the different genes already associated with ASD in the pathogenesis of the disease.
Highlights
Autism spectrum disorder (ASD) is defined as a group of clinical heterogeneous disorders characterized by deficits in social behaviors and communication, restricted interests, and repetitive behaviors, often accompanied by other impairments, such as intelligence and language deficits [1]
Many studies based on chromosomal microarray, targeted gene sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS) identified hundreds of genes associated with autism risk [6–10], demonstrating that there are several complex genetic factors that contribute to ASD risk
Filtering was carried out by applying a series of steps: low-quality variants were filtered out (Qscore threshold of 100); variants with a minor allele frequency (MAF) ≥1% in the GnomAD database were discarded, and we focused on predicted missense, frame-shift, stop-gain or stop-loss, and splicesite variants
Summary
Autism spectrum disorder (ASD) is defined as a group of clinical heterogeneous disorders characterized by deficits in social behaviors and communication, restricted interests, and repetitive behaviors, often accompanied by other impairments, such as intelligence and language deficits [1]. Many studies based on chromosomal microarray, targeted gene sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS) identified hundreds of genes associated with autism risk [6–10], demonstrating that there are several complex genetic factors that contribute to ASD risk. Our ability to identify causative genetic risk factors in a single individual is still not satisfactory, and our understanding of the role played by these variants in the causation of diseases, those inherited from seemingly unaffected parents, remains limited. The effort to identify the genetic background that causes or contributes to ASD symptoms could be hampered by studies on non-homogeneous patients, such as studies involving both complex and essential ASD. Our goals were to evaluate the presence of rare inherited or de novo genetic variants in all patients and their parents, when possible, in order to determine their role in ASD onset. We did not take into consideration common variants (shared with more than 1% of the human population), and we focused only on those with possible pathogenetic roles that are not present in the family genetic background
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