m⁶A-mRNA Reader YTHDF2 Identified as a Potential Risk Gene in Autism With Disproportionate Megalencephaly

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with diverse genetic underpinnings.
• A subset of autistic individuals exhibits disproportionate megalencephaly (ASD-DM) by age three, often associated with intellectual disability and poorer long-term outcomes.
• The genetic factors contributing to ASD-DM remain largely undefined, hindering targeted interventions.

Purpose of the Study:

• To identify novel candidate genes associated with ASD-DM.
• To elucidate the genetic etiology of this severe autism subphenotype.
• To explore potential molecular mechanisms, including RNA modification pathways.

Main Methods:

• Expanded a cohort of ASD-DM individuals to 766 probands from the Autism Phenome Project and Simons Simplex Collection.
• Performed whole-exome sequencing and analyzed de novo protein-impacting variants.
• Utilized functional network analysis and zebrafish models to investigate candidate gene function (e.g., YTHDF2, YTHDC1).

Main Results:

• Identified 154 candidate ASD-DM genes, including 14 high-confidence autism genes and seven previously linked to DM.
• Five genes (e.g., CHD8, PTEN) were associated with both autism and DM.
• Functional studies in zebrafish implicated the m6A-RNA reader YTHDF2 in regulating head/brain size and Fragile X-related gene expression, suggesting a role in autistic phenotypes. A variant in YTHDC1 was also found.

Conclusions:

• The study significantly expands the list of candidate genes for ASD-DM, providing a more comprehensive genetic landscape.
• Findings implicate the m6A-RNA modification pathway as a potential contributor to the pathophysiology of severe autism with megalencephaly.
• Further research into these genes and pathways may reveal novel therapeutic targets for ASD-DM.