Dystrophin genetic variants and autism

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Muscular Dystrophy

Background:

• Loss-of-function variants in the dystrophin gene cause muscular dystrophies and are increasingly recognized as a risk factor for autism spectrum disorder (ASD).
• While intellectual disability is a known comorbidity in Duchenne (DMD) and Becker muscular dystrophy (BMD), the specific link between dystrophinopathies and ASD is a more recent finding.
• The correlation between specific dystrophin gene mutations (genotype) and ASD symptoms (phenotype) remains unclear, necessitating further investigation.

Purpose of the Study:

• To review the existing literature on ASD prevalence in individuals with dystrophinopathies.
• To examine the role of different dystrophin gene isoforms in the etiology of ASD.
• To investigate the influence of genetic background on the development of ASD in patients with DMD/BMD.

Main Methods:

• Literature review focusing on ASD prevalence, dystrophin isoforms, and genetic background in dystrophinopathies.
• Case reports of four families with individuals affected by both ASD and DMD/BMD, including monozygotic twins and triplets.
• Whole exome sequencing of individuals with ASD and DMD/BMD to identify potential genetic variants.

Main Results:

• Preliminary data suggest a complex and heterogeneous genetic architecture for ASD in dystrophinopathies, involving rare variants with significant effects.
• The study identified two unrelated individuals with ASD and poorly characterized dystrophin variants, indicating potential brain-specific effects.
• Analysis of familial cases, including discordant and concordant twins, highlights the intricate genetic factors contributing to ASD in this population.

Conclusions:

• The genetic basis of ASD in dystrophinopathies is multifaceted, involving various dystrophin variants and modifier genes.
• Rare dystrophin variants may disproportionately affect brain development, contributing to ASD phenotypes.
• Establishing a consortium for genomic studies in ASD-DMD/BMD patients is crucial for elucidating the genetic landscape of ASD in these conditions.