The ultimate vision of this comprehensive program is the establishment of a data commons – a national repository of detailed information on individuals with variants in genes thought to be involved in intellectual and developmental disabilities.
The economic, societal and personal costs of intellectual and developmental disabilities are devastating. Accessibility of human genetic and genomic information and the computing power to analyze massive data stores has matured rapidly in the past quarter century. While genomic tests are being more readily performed, families need support in understanding what a gene variant actually means . We believe that critical answers lie hidden in genetic information, neurobehavioural reports, brain scans and other electronic health information scattered throughout the country. We are confident that combining and curating this information and applying sophisticated methods of analysis will help identify underlying mechanisms of neurodevelopmental disorders. This is the critical path to finding treatments or preventative measures.
In this quest, we have three mutually reinforcing goals, each led by a BGR Lead Institution. The overall effort is led by Principal Investigator, Philip Payne, PhD, FACMI, at Washington University, and governed by a single IRB.
Standardize the Assessment
Our understanding of the link between rare gene variants and neurodevelopmental disorders is limited by the lack of standardization of phenotypic information to accompany clinical genomic data. Standardizing the way we obtain such information will enhance our ability to associate a genetic profile with its outward presentation in the individual. The BGR assessment tool, the RNAP (Rapid Neurobehavioral Assessment Protocol), allows us to measure and describe factors including cognitive ability, adaptive function, sensory-motor function, psychiatric symptoms, physical features and neurologic symptoms. The RNAP is optimized to be implemented virtually in a clinical setting by generalist clinicians across medical specialties. This tool has been developed and designed by experts at the University of North Carolina at Chapel Hill and has been deployed across all participating institutions. In Aim 1, we will validate this tool against previous neurobehavioral records.
Curate the Genes
There are hundreds of genes, with varying levels of evidence, thought to be involved in neurodevelopmental disorders. In collaboration with ClinGen and our participating sites, we will accelerate the evaluation of such genes for the level of evidence for involvement in neurodevelopmental disorders. The Boston Children’s Hospital/Harvard Medical School team has led the selection of putative brain genes of the highest priority and established a framework for future gene nominations for the BGR. Individuals with clinically-identified variants classified as pathogenic, likely pathogenic or variants of uncertain significance in these genes will be invited to participate in the Brain Gene Registry. In Aim 2, The new Intellectual Disability / Autism Gene Curation Expert Panel, led by the BCH / HMS team, will leverage information from the BGR, including the standardized neurobehavioral test results and the electronic health record data, for advanced brain gene curation.
Build the Registry
The Brain Gene Registry is born from the idea that if we aggregate information on individuals with rare gene variants, answers about the role of such variants in intellectual and developmental disorders, will likely emerge. In Aim 3, with state of the art data informatics overseen by the team at Washington University, the Registry will pool information from our innovative neurobehavioral assessment and data from the electronic health record, together with genetic test reports. This will be a critical resource for brain gene curation (evaluating the evidence of the role of a gene in neurodevelopment) and genotype-phenotype correlation (the relationship between a rare gene variant and its outward manifestation). Furthermore, the Registry will be a precious asset for future translational research efforts, including natural history studies and clinical trials, as we work together to share information on cohorts of individuals with rare genetic neurodevelopmental diseases.