Repiská Gabriela, Konečný Michal, Krasňanská Gabriela, Celušáková Hana, Belica Ivan, Rašková Barbara, Kopčíková Mária, Keményová Petra, Ostatníková Daniela, Lakatošová Silvia
Institute of Physiology, Academic Center for Autism Research, Faculty of Medicine, Comenius University in Bratislava, 813 72 Bratislava, Slovakia.
Laboratory of Genomic Medicine, GHC GENETICS SK s.r.o., 841 04 Bratislava, Slovakia.
Genes (Basel). 2025 Jul 28;16(8):893. doi: 10.3390/genes16080893.
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by a complex, multifactorial etiology with a strong genetic contribution. Our study aimed to evaluate the link between the burden of rare genetic variants within a specific panel of ASD and intellectual disability-associated genes and phenotypic variability in a cohort of children with autism in Slovakia.
Gene burden scores were calculated based on pathogenic, likely pathogenic, and uncertain significance rare DNA variants identified by whole-exome sequencing. We then assessed the effect of three different scoring methods on the variance across 15 psycho-behavioral parameters describing the phenotypic profiles of 117 ASD probands.
The burden score showed a significant multivariate effect on the combination of psycho-behavioral parameters. This score was associated with the social affect of ADOS-2, as well as with the socialization domain, and total adaptive behavior scores from the Vineland Adaptive Behavior Scales-3 (VABS). While a score based solely on count of pathogenic and likely pathogenic variants did not show a multivariate effect, incorporating variants of uncertain significance revealed a multivariate effect on two adaptive behavior parameters: daily living skills and total adaptive behavior score (VABS).
Our findings partially explain the variability in phenotypic manifestation in our ASD patient cohort, highlighting the importance of considering the cumulative effect of rare genetic variants, including those of uncertain significance, in shaping the diverse clinical presentation of ASD.
自闭症谱系障碍（ASD）是一组异质性神经发育障碍，其病因复杂、多因素，且有很强的遗传因素。我们的研究旨在评估斯洛伐克一组自闭症儿童中，特定ASD和智力残疾相关基因面板内罕见遗传变异的负担与表型变异性之间的联系。
基于全外显子测序鉴定出的致病、可能致病及意义不确定的罕见DNA变异计算基因负担评分。然后，我们评估了三种不同评分方法对描述117名ASD先证者表型特征的15个心理行为参数方差的影响。
负担评分对心理行为参数的组合显示出显著的多变量效应。该评分与ADOS-2的社会情感相关，也与社会交往领域以及文兰适应行为量表-3（VABS）的总适应行为评分相关。虽然仅基于致病和可能致病变异计数的评分未显示多变量效应，但纳入意义不确定的变异后，显示出对两个适应行为参数的多变量效应：日常生活技能和总适应行为评分（VABS）。
我们的研究结果部分解释了我们的ASD患者队列中表型表现的变异性，强调了在塑造ASD多样临床表现时考虑罕见遗传变异（包括意义不确定的变异）累积效应的重要性。
