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

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Dystrophinopathies

Background:

• Duchenne and Becker Muscular Dystrophy (DMD/BMD) are dystrophinopathies affecting males, often co-occurring with neurodevelopmental disorders (NDDs) like autism spectrum disorder (ASD) and intellectual disability (ID).
• The low penetrance of NDDs in dystrophinopathies indicates that additional genetic factors are involved.
• Understanding the genetic architecture of ASD in DMD/BMD is crucial for improved diagnosis and therapeutic strategies.

Purpose of the Study:

• To investigate the genetic underpinnings of ASD in individuals with dystrophinopathies.
• To identify genetic variants associated with ASD and ID in DMD/BMD patients.
• To explore the role of de novo variants (DNVs) and rare risk variants (RRVs) in the manifestation of ASD in dystrophinopathies.

Main Methods:

• Clinical evaluation and categorization of 83 individuals with dystrophinopathies into ASD, ID risk, and control groups.
• Whole exome sequencing to identify de novo variants (DNVs) and rare risk variants (RRVs).
• Statistical analysis to assess variant enrichment and correlation with clinical phenotypes and paternal age. Gene ontology analysis was performed.

Main Results:

• Enrichment of risk de novo variants (DNVs) was observed in individuals with ASD and dystrophinopathies (ASD-DMD), with DNVs correlating with paternal age.
• DMD-ASD individuals exhibited a higher average of rare risk variants (RRVs) compared to controls.
• Gene ontology analysis revealed enrichment of extracellular matrix-related genes, including collagens and Ehlers-Danlos syndrome genes, in ASD-DMD and DMD-ID groups.

Conclusions:

• Findings support an oligogenic model for ASD in dystrophinopathies, where multiple genetic factors contribute to the phenotype.
• The study highlights the importance of analyzing homogenized samples to unravel the complex genetic architecture of ASD in dystrophinopathies.
• Investigating additional genetic contributors beyond DMD variants is essential for understanding NDDs in these conditions.