Simon T. Schafer and Fred H. Gage; PNAS May 11, 2021 118 (19) e2104888118

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder that is thought to emerge very early in development. Cerebral overgrowth, which is clinically referred to as macrocephaly, is frequently observed in children with ASD, and brain imaging studies have reported increases in both gray- and white-matter volume. Children with these early signs of brain enlargement have been shown to be part of an ASD group with high probability of receiving a diagnosis. The presence of additional numbers of neurons and increased cortical thickness in the prefrontal cortex of the postmortem brain from ASD patients complement these clinical observations. Copy number variation (CNV) in the 16p region of chromosome 16 has been linked to ASD and can manifest in opposing head sizes. Deletion of 16p11.2, which is probably one of the most well-known CNVs linked to ASD, generally leads to macrocephaly, whereas duplications in this region have been associated with smaller head sizes. The cellular mechanisms that underlie these opposing phenotypes remain unknown.

How an overproduction or overabundance of progenitor cells during early brain development can lead to structural and functional alterations that are associated with ASD at later stages is currently not known. Thus, future studies may need to establish how the observed neurodevelopmental alterations unfold as the brain matures. Forthcoming technological advancements and clinically well-defined stem cell–based disease models may allow us to disentangle the cellular mechanisms underlying specific endophenotypes related to ASD at a finer level of granularity. As therapeutic interventions are still far from being specific, the findings of this current study point to a new and promising direction for targeting amenable clinical endophenotypes in ASD, thereby providing a window of opportunity for intervention or mitigation of symptoms. Future studies that explore the specificity of these mechanisms for ASD and in the context of macrocephaly will undoubtedly further advance the field.

See: https://www.pnas.org/content/118/19/e2104888118