Program 1Discovering the mechanisms of rare neurodevelopmental disorders
Finding variants has become far easier, but determining which are causal, and how, is now the real bottleneck.
- Patient variant
- Gene function
- Disease mechanism
- Patient groups
- Tailored therapy
Genome sequencing has uncovered large numbers of variants suspected to cause rare neurodevelopmental disorders, yet few are confirmed, and many remain variants of uncertain significance, often in genes whose roles in brain development are unknown. We address this gap by uncovering what each affected gene does in the developing brain and how patient variants alter its function. This work provides the functional foundation for establishing genotype–phenotype relationships, through joint efforts with clinical geneticists locally and internationally. Because variants in the same gene can disrupt its protein in distinct ways, defining the effect of each variant allows patients to be grouped by mechanism, a step toward therapies tailored to each group.
Why it matters
- Resolves variants of uncertain significance with functional evidence, supporting genetic diagnosis
- Explains why patients carrying variants in the same gene can present with different clinical features
- Groups patients by the disease mechanism they share, guiding the design of tailored therapies
- Provides patient-derived cell and mouse models that serve as platforms for testing new treatments
