Autism spectrum disorder (ASD) is a developmental disability caused by differences in the brain and affects ~1 in 31 (3.2%) children aged 8 years, with it 3 times more common among boys. Individuals with ASD may behave, communicate, interact and learn in ways that are different from most other people. However, the abilities of people with ASD can vary dramatically.
ASD arises from a complex interplay of genetic, molecular and neurodevelopmental factors, and researchers are increasingly uncovering the intricate biological pathways that contribute to its onset and progression. At this year’s American Society of Human Genetics (ASHG) annual meeting, a dedicated session will explore cutting-edge approaches to investigating the molecular basis of ASD. Attendees can expect discussions on coding and non-coding genetic variation, shared genetic architecture with other psychiatric disorders and key molecular and functional vulnerabilities that may underlie ASD.
One study to be presented focuses on the cerebellum, the largest part of the hindbrain. Once thought to be relevant only for motor control and balance, it is now recognized as playing a key role in higher-order cognitive functions and is increasingly implicated in ASD research.
Researchers will share findings on how chromodomain-helicase-DNA-binding protein 8 (CHD8), a chromatin remodeler strongly associated with ASD, influences cerebellar development and function. Their work reveals that disruptions in CHD8 expression affect neuronal circuit formation during development and lead to persistent functional vulnerabilities in adulthood.
Ahead of the conference, Technology Networks spoke with Dr. Cesar Canales, an assistant professional researcher at the University of California (UC) Davis Center for Neuroscience, to learn more about these molecular insights and how they are reshaping our understanding of ASD’s biological underpinnings.
Isabel Ely, PhD (IE):
Science Writer
Technology Networks
Isabel is a Science Writer and Editor at Technology Networks . She holds a BSc in exercise and sport science from the University of Exeter, a MRes in medicine and health and a PhD in medicine from the University of Nottingham. Her doctoral research explored the role of dietary protein and exercise in optimizing muscle health as we age.
How has our understanding of the genetic and molecular underpinnings of ASD evolved over the past decade?
Cesar Canales, PhD (CC):
Assistant Professional Researcher
University of California, Davis
Dr. Cesar Canales is a developmental biologist and interdisciplinary research scientist with a strong interest in the molecular mechanisms, gene regulatory programs and environmental factors that influence normal and aberrant neurodevelopment.
Over the past decade, our understanding of ASD has shifted from focusing on single-gene causes toward a broader view of convergent biological mechanisms. We now know that hundreds of genes contribute to ASD risk, but many converge on a common set of neurodevelopmental pathways – particularly those regulating chromatin remodeling, transcriptional control, synaptic development and neuronal signaling. Large-scale genomic studies, including exome and genome sequencing, have revealed that ASD risk is heavily driven by rare, highly penetrant de novo mutations in genes that play essential roles in early brain development.
At the same time, advances in functional genomics and single-cell technologies have helped us move beyond identifying variants to understanding how they alter gene regulation, cell identity and neural circuit formation. This has been transformative, allowing us to connect genotype to phenotype in ways that weren’t possible even a few years ago.
IE:
Science Writer
Technology Networks
Isabel is a Science Writer and Editor at Technology Networks . She holds a BSc in exercise and sport science from the University of Exeter, a MRes in medicine and health and a PhD in medicine from the University of Nottingham. Her doctoral research explored the role of dietary protein and exercise in optimizing muscle health as we age.
ASD is known for its heterogeneity – both genetically and behaviorally. How can studying genes like CHD8 help us disentangle this complexity?
CC:
Assistant Professional Researcher
University of California, Davis
Dr. Cesar Canales is a developmental biologist and interdisciplinary research scientist with a strong interest in the molecular mechanisms, gene regulatory programs and environmental factors that influence normal and aberrant neurodevelopment.
CHD8 provides a powerful entry point for understanding ASD heterogeneity because it acts as a master regulator of neurodevelopmental gene networks. Individuals with CHD8 mutations share a recognizable clinical profile, often including macrocephaly, social-communication challenges and cognitive features, which defines a relatively homogeneous ASD subtype.
By studying CHD8, we can uncover core molecular mechanisms, for example, chromatin remodeling, transcriptional control of synapse-related genes and timing of neurogenesis, that may also be perturbed in other ASD-associated genes. In other words, CHD8 serves as a biological anchor, helping us map shared pathways across genetically diverse forms of ASD. This approach can reduce the apparent heterogeneity by identifying convergent molecular signatures that underlie overlapping clinical features.
IE:
Science Writer
Technology Networks
Isabel is a Science Writer and Editor at Technology Networks . She holds a BSc in exercise and sport science from the University of Exeter, a MRes in medicine and health and a PhD in medicine from the University of Nottingham. Her doctoral research explored the role of dietary protein and exercise in optimizing muscle health as we age.
CHD8 has become one of the most prominent ASD-associated genes. Why do you think it plays such a central role compared to others?
CC:
Assistant Professional Researcher
University of California, Davis
Dr. Cesar Canales is a developmental biologist and interdisciplinary research scientist with a strong interest in the molecular mechanisms, gene regulatory programs and environmental factors that influence normal and aberrant neurodevelopment.
CHD8 stands out for several reasons. First, mutations in the CHD8 gene are highly penetrant and consistently lead to ASD diagnoses, which is rare among neurodevelopmental genes. Second, CHD8 functions as a chromatin remodeler, controlling the expression of hundreds of downstream genes, many of which are themselves implicated in ASD. This gives CHD8 a network-level influence on neurodevelopmental programs.
This protein is also expressed broadly during early cortical development, influencing processes like neural progenitor proliferation, cell fate specification and synaptic maturation. Because of this central position in regulatory hierarchical processes, disrupting CHD8 has cascading effects across multiple cell types and developmental stages. That systemic influence likely explains why CHD8 mutations produce a well-defined ASD subtype and have become a major focus for disease-modeling efforts.
IE:
Science Writer
Technology Networks
Isabel is a Science Writer and Editor at Technology Networks . She holds a BSc in exercise and sport science from the University of Exeter, a MRes in medicine and health and a PhD in medicine from the University of Nottingham. Her doctoral research explored the role of dietary protein and exercise in optimizing muscle health as we age.
Which insights from your latest work do you believe the ASD field should pay attention to?
CC:
Assistant Professional Researcher
University of California, Davis
Dr. Cesar Canales is a developmental biologist and interdisciplinary research scientist with a strong interest in the molecular mechanisms, gene regulatory programs and environmental factors that influence normal and aberrant neurodevelopment.
Part of our latest work in the Nord Neurogenomics Lab at UC Davis Center for Neurosciences, which I’ll be presenting at ASHG, focuses on the cerebellar impact of CHD8 haploinsufficiency, an area that has received far less attention compared to cortical studies. Using single-nucleus transcriptomic and chromatin accessibility profiling, we’re mapping how CHD8 loss alters cell-type-specific gene expression programs across cerebellar development.
In close collaboration with Dr. Diasynou Fioravante, a leading cerebellar neurophysiologist, we are uncovering a clear pattern of cell-type vulnerability, particularly among Purkinje neurons, oligodendrocytes and interneuron populations, accompanied by transcriptional signatures linked to synaptic regulation, RNA processing and mitochondrial function. Combined with electrophysiological and behavioral assays from the Fioravante lab, these findings suggest that the cerebellum may play a more central role in CHD8-linked ASD pathology than previously appreciated, contributing to both motor and cognitive phenotypes observed in patients.
By extending CHD8 studies beyond the cortex, our work provides a systems-level perspective on how ASD risk genes shape distributed brain networks. This, in turn helps to lay the groundwork for region and cell-type-specific therapeutic strategies.
IE:
Science Writer
Technology Networks
Isabel is a Science Writer and Editor at Technology Networks . She holds a BSc in exercise and sport science from the University of Exeter, a MRes in medicine and health and a PhD in medicine from the University of Nottingham. Her doctoral research explored the role of dietary protein and exercise in optimizing muscle health as we age.
How do you see the field evolving in the next 5–10 years, especially in integrating genetics, neurobiology and behavior?
CC:
Assistant Professional Researcher
University of California, Davis
Dr. Cesar Canales is a developmental biologist and interdisciplinary research scientist with a strong interest in the molecular mechanisms, gene regulatory programs and environmental factors that influence normal and aberrant neurodevelopment.
Over the next decade, I think we’ll see the field move toward a truly multiscale understanding of ASD – linking genetic variation, cellular states and circuit-level dynamics to specific behavioral phenotypes. Single-cell and spatial transcriptomics will continue to be key, but integration with functional imaging, electrophysiology and computational modeling will allow us to map how molecular disruptions reshape neural networks in real time.
At the same time, iPSC-derived systems, including organoids and assembloids, will help bridge human genetics with model organism studies. Ultimately, the goal is not only to define molecular mechanisms but also to predict functional outcomes, which will be critical for designing targeted, precision-based interventions.
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