Rare Variant Burden and Behavioral Phenotypes in Children with Autism in Slovakia

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Behavioral Science

Background:

• Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a significant genetic basis.
• Understanding the genetic underpinnings of ASD is crucial for explaining its diverse phenotypic presentations.

Purpose of the Study:

• To investigate the relationship between the burden of rare genetic variants in ASD-associated genes and phenotypic variability in Slovakian children with ASD.
• To assess the impact of different genetic variant scoring methods on psycho-behavioral parameters.

Main Methods:

• Whole-exome sequencing was used to identify rare DNA variants.
• Gene burden scores were calculated using pathogenic, likely pathogenic, and uncertain significance variants.
• The effect of these scores on 15 psycho-behavioral parameters was analyzed in 117 ASD probands.

Main Results:

• A significant multivariate effect of the gene burden score was observed on a combination of psycho-behavioral parameters, including social affect (ADOS-2) and adaptive behavior (VABS).
• While pathogenic and likely pathogenic variants alone did not show a multivariate effect, incorporating variants of uncertain significance revealed an impact on daily living skills and total adaptive behavior scores.

Conclusions:

• The cumulative effect of rare genetic variants, including those of uncertain significance, helps explain the phenotypic variability in ASD.
• These findings underscore the importance of considering a broader spectrum of genetic variants in understanding the diverse clinical manifestations of ASD.