Understanding rare variant contributions to autism: lessons from dystrophin-deficient model

Abstract

Duchenne and Becker Muscular Dystrophy are dystrophinopathies with a prevalence of 1:5000-6000 males, caused by pathogenic variants in DMD. These conditions are often accompanied by neurodevelopmental disorders (NDDs) like autism (ASD; ~20%) and intellectual disability (ID; ~30%). However, their low penetrance in dystrophinopathies suggests additional contributing factors. In our study, 83 individuals with dystrophinopathies were clinically evaluated and categorized based on ASD (36 individuals), ID risk (12 individuals), or controls (35 individuals). Exome sequencing analysis revealed an enrichment of risk de novo variants (DNVs) in ASD-DMD individuals (adjusted p value = 0.0356), with the number of DNVs correlating with paternal age (p value = 0.0133). Additionally, DMD-ASD individuals showed a higher average of rare risk variants (RRVs) compared to DMD-Controls (adjusted p value = 0.0285). Gene ontology analysis revealed an enrichment of extracellular matrix-related genes, especially collagens, and Ehlers-Danlos syndrome genes in ASD-DMD and DMD-ID groups. These findings support an oligogenic model for ASD in dystrophinopathies, highlighting the importance of investigating homogenized samples to elucidate ASD's genetic architecture.

Fig. 1. Distribution of total and risk DNVs and differences in paternal age between groups.

a Bar plot showing the distribution of total and risk DNVs in DMD-ASD and DMD-Control groups. Fishers’ exact test was used to test whether there was a difference between groups regarding total and risk DNVs. b Boxplot showing the distribution of paternal age between DMD-ASD and DMD-Control groups. Welch’s t test was applied to determine whether there was a difference in the mean paternal age. c Boxplot showing the distribution of rare variants for each group. Mann–Whitney test was performed to verify whether there was a difference in the average number of RRVs and synonymous variants between cases (DMD-ASD and DMD-ID) and the DMD-Control group. The DMD-ASD group presented, on average, a higher number of RRVs than DMD-Controls, after Bonferroni correction. ns = non-significant; *p value < 0.05.