Every year, millions of children are born with neurodevelopmental disorders that can affect their communication, learning, behavior, and social interactions. These developmental delays can lead to lifelong challenges for both the child and their families. Compounding these challenges is the fact that many of these disorders are hard to diagnose, leaving children and their families searching for answers.
Thanks to advances in genomic technology, it is now clear that many neurodevelopmental disorders are caused by changes in an individual’s genome that interfere with critical developmental processes. Two labs at HudsonAlpha focus their research on better understanding the genetic basis of neurodevelopmental disorders. Their goal is to help families receive a faster diagnosis, support from the moment of diagnosis, and the knowledge and tools they need to navigate their health journey with greater confidence.
Ending the diagnostic odyssey one genome at a time
Geneticists have identified over 1,500 genes associated with neurodevelopmental disorders. Although this helps about one-third of patients with neurodevelopmental diseases receive a genetic diagnosis, hundreds of thousands of patients remain without an answer. There are likely still thousands of undiscovered genetic contributors to neurodevelopmental diseases.
HudsonAlpha Faculty Investigator Greg Cooper, PhD, and his lab are experts at using genome sequencing to revolutionize the diagnosis of rare neurodevelopmental disorders while also identifying new genetic contributors to these disorders. Since 2013, Cooper and his lab have sequenced the genomes of nearly 2,000 children, providing over 40 percent with a genetic finding that may be relevant to their symptoms. In addition, the lab has helped identify more than 25 new gene-disease associations, adding important information to geneticists’ diagnostic toolkit.
Since 2013, Cooper and his lab have sequenced and analyzed the genomes of nearly 2,000 children, providing over 40 percent with a genetic finding that may be relevant to their symptoms.
Over the past decade, Cooper’s lab has kept up with advancing technology, adjusting their sequencing methods from exome sequencing to short-read genome sequencing to the newest technology, long-read genome sequencing. Long-read genome sequencing provides a far more comprehensive view of the genome, allowing scientists to identify many genetic variants that traditional sequencing methods may miss. One type of variation that shows great promise in diagnosing rare diseases is structural variants. These include large deletions, duplications, inversions, translocations, and more complex events that can disrupt gene function, resulting in diseases.
Dr. Cooper and his team feel confident that they will identify many variants with long-read genome sequencing that might be responsible for some individuals’ symptoms. In a study recently published in Genome Research, the Cooper lab performed long-read genome sequencing on 96 individuals who had received no diagnostic results from short-read sequencing. New disease-relevant or potentially relevant genetic findings were identified in sixteen individuals (16%), eight of which had pathogenic or likely pathogenic variants.
Because of the promising results from this study, Cooper and his lab were awarded a five-year, $2.9 million National Institutes of Health (NIH) grant to use long-read sequencing to re-sequence hundreds of genomes from individuals who previously had genome sequencing with no diagnostic results. In addition to potentially helping diagnose dozens of individuals, the study will allow computational biologists in the Cooper lab to continue updating and improving their analysis pipeline to identify more genetic variants in future individuals.
Discovering targets for better quality-of-life treatments
HudsonAlpha’s newest faculty investigator, Andrew Kodani, PhD, aims to use genetics to better understand healthy brain development and what goes wrong in neurodevelopmental diseases. Koanid and his lab work closely with clinicians and patient groups to identify genetic causes of disease in cohorts of patients with similar conditions.
Once a potential genetic contributor is identified, the team uses various experimental systems to validate its role in neurodevelopment, a complex process involving intricate interactions between various developmental signaling pathways that regulate the proliferation, differentiation, and migration of neural stem cells. They are particularly interested in the WNT and mTOR signaling pathways, which regulate neural progenitor cell proliferation in the developing brain. Disruptions in these pathways during development can lead to brain size and function abnormalities, as seen in conditions like autism spectrum disorder and microcephaly.
The Kodani lab aims to better understand how genetic changes in neurodevelopmental disorders disrupt these signaling pathways and contribute to brain disease. By targeting these pathways, they hope to develop new therapies that can improve cognitive and social behavioral issues in individuals with neurodevelopmental disorders.
Genetic and molecular information opens numerous doors for individuals and their families. It allows them to seek out resources, patient groups, and, most importantly, potential treatment options. The Kodani lab helps patients diagnosed with rare neurodevelopmental disorders by connecting them with appropriate physicians, hospitals running clinical trials, and support groups. Receiving care from a specialist allows individuals to receive specific interventions to improve their quality of life.
Non-pharmaceutical interventions like therapy help improve the quality of life for some patients, but often, patients benefit most from drug treatment. The Kodani lab uses genetic and molecular information to identify potential drug treatments (including clinical trials) for patients with rare diseases.
Sometimes, that is as simple as identifying an existing drug that will help the patient. By screening hundreds of thousands of drugs in publicly available drug libraries, Kodani and his lab try to find potential compounds that will help re-establish the signaling pathways that went awry in neurodevelopmental diseases. Their ultimate goal is to repurpose FDA-approved drugs for use in patients with rare diseases. In other cases, the scientists get creative and look toward natural compounds or dietary changes that could modulate the broken pathway, thus improving the quality of life in individuals with neurodevelopmental disorders.
