neuroDEVELOPMENTS

New techniques to decipher autism’s complexity

Following an initial focus on genetic risk for psychiatric disorders widely distributed in the human population, contemporary studies increasingly emphasize the role of rare de novo somatic mutation in both coding and regulatory regions of the genome. In this issue, our newsletter highlights the promise and challenges of these advances. De novo mutation in autism spectrum disorder (ASD) was first convincingly shown using exome- and other-directed sequencing strategies. Here, in our first paper, technical advance using ultra-deep whole genome sequencing reveals the prevalence of mosaic somatic mutation in the cortex of ASD patients and controls (Rodin, Dou et al 2021). Alongside the advances in sequencing chemistry and data analytics that better define mutation, the consequential altered phenotype is being directly assessed by recombineering the human risk genes in a growing number of models. To illustrate the speed of advance in phenotyping, we focus secondly on a recent study where the growing power of CRISPR-based gene engineering is employed to systematically alter multiple risk loci and assess phenotypic mechanisms in mouse embryos (Jin et al 2020). In this pioneering study the authors focused on de novo mutation occurring within coding regions predicted to be highly penetrant. These papers and the comments of our Board members emphasize the continued rapid advance linking both germ line and de novo mutation to phenotype in human neurodevelopmental disorders.

-Ron McKay, PhD, Chief Editor
Lieber Institute for Brain Development

-Venkata S. Mattay, MD
Managing Editor

-Michele Solis, PhD
Science Writer