OtherAutism research : official journal of the International Society for Autism Research2025

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

Sierra S Nishizaki, Nicholas K Haghani, Gabriana N La and 8 others

PMID 39887636

WHAT IT FOUND

Researchers identified YTHDF2 as a candidate risk gene for autism with disproportionate head growth.

In zebrafish, adding this gene increased brain size, while removing it reduced brain size. This is genetic mechanism research, not a clinical test or treatment.

Key findings

01The study identified 154 candidate genes for autism with large head size, including YTHDF2, which was found to have a duplication in a single patient with disproportionate head growth.

02In zebrafish models, overexpression of YTHDF2 resulted in increased head and brain size, while knocking down the gene resulted in smaller brains, suggesting the gene dosage affects brain growth.

STILL TO COME

How it was doneWhat they found

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What it does not show

The study found a genetic link in only one patient for the key gene YTHDF2, so it cannot show how common this is. Most patients were identified by head circumference, not MRI, so they may not have had the specific brain-growth pattern the study aimed to find. Zebrafish brains are very different from human brains, so results in fish may not translate to humans. The study did not find a statistically significant increase in genetic disruptions in the autism groups compared to control siblings.

Declared interests

The authors declared no conflicts of interest. The work was funded by several National Institutes of Health institutes.

The easy way to misread this

Do not assume YTHDF2 testing is clinically useful or that this explains most cases of autism with large heads. The effect was seen in one patient and in zebrafish, and the study did not find a significant overall genetic difference between the autism groups and their typically developing siblings.

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The study

Participants
766 probands (11 with disproportionate megalencephaly, 755 with macrocephaly) and zebrafish models
Certainty of evidence
Low

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    Cite

    Sierra S Nishizaki, Nicholas K Haghani, Gabriana N La, et al. m6A-mRNA Reader YTHDF2 Identified as a Potential Risk Gene in Autism With Disproportionate Megalencephaly. Autism research : official journal of the International Society for Autism Research. 2025.

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