New gene linked to brain size in people with autism | Spectrum


Heads up: Zebrafish that overexpress the YTHDF2 gene (bottom) have an unusually large head, while those without the gene (top) have a small one, compared to controls (middle).

A gene that was not previously linked to autism may contribute to a form of the disease marked by a unusually large brain.

Sierra Nishizakipostdoctoral researcher in Megan Dennis‘ at the University of California, Davis MIND Institute, presented the findings Thursday at the 2022 annual meeting of the International Society for Autism Research. (Links to abstracts may only work for registered conference attendees.)

About 15% of autistic boys, compared to 4% of non-autistic boys, have a disproportionate brain for their size, a condition known as megalencephaly. Their brains remain large throughout childhood, the team has previously shown. These boys also have low IQs and are minimally verbal, Nishizaki says, and may represent an autism subtype with distinct genetic backgrounds.

To analyze these origins, the researchers identified 17 de novo variants — mutations not inherited from parents — in 100 autistic people with megalencephaly or its surrogate, macrocephaly, a large head. One of the variants also affects the size of the zebrafish’s head, the team found.

“One of the big challenges in studying autism genetics in general is the immense heterogeneity,” says Nishizaki. “There are so many genes associated with different autism traits. One way to identify more is to sub-phenotype.”

Jhe researchers identified variants of 18 genes in 11 autistic people from Project on the phenomenon of autismwhich includes data on megalencephaly, and 89 autistic people from Simons Simplex collection, which measures macrocephaly. (The Simons Simplex collection and Spectrum are both funded by the Simons Foundation.) They then edited mutations in 10 of the zebrafish genes, which have a transparent head, allowing easy brain measurements.

Knocking out the YTHDF2 gene gave the fish an unusually small head. Overexpression of the gene – similar to a variant found in one of the autistic participants – increased head size.

“We are convinced that it is a gene associated with head size, probably also associated with their autism,” says Nishizaki.

Variants in a second gene, RYR3, also reduced head size, but understanding its mechanisms will require “further research”, said Nishizaki, adding that the team plans to test the rest of the genes in the zebrafish.

Read more reports of the 2022 International Autism Research Society annual meetg.

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