Brain malformations comprise a group of genetic developmental brain disorders that present in childhood with intellectual disability and epilepsy and other neurologic features, causing substantial morbidity, mortality, and health care costs. To date, over 1000 genes have been associated with brain malformations. The long term goal of this project is to create a resource of well-categorized and expertly curated genes and variants responsible for causing brain malformations, to help clinicians navigate diagnosis and inform management. To this end we have assembled a group of clinician-investigators with broad, complementary expertise in brain malformations in the domains of gene discovery, neurobiology, clinical phenotype, radiographic presentation, and treatment. We have also included experts in bioinformatics and colleagues deeply involved in ClinGen and ClinVar to facilitate integration of our findings into these existing organizational frameworks. Important for this proposal, our group is comprised of individuals with a long-standing history of collaboration across institutions, nations, and generations.
In Aim 1 of this proposal we will survey the literature to curate genes associated with brain malformations, assess the strength of the evidence for these associations using ClinGen criteria, and organize them into biologically and clinically useful groups.
In Aim 2 of this proposal, we will extend our efforts to curate variants encountered in clinical and research exomes recruited via the Brain Development and Genetics Clinic, a specialty multidisciplinary clinic at Boston Children?s Hospital devoted to the diagnosis, treatment and counseling of patients with brain malformations. Variant interpretations will be contributed to ClinVar.
In Aim 3 of this proposal, we will perform deep curation of genes and variants from the literature and publicly available databases for clinically important subgroups of brain malformations, including those associated with focal cortical dysplasia (FCD), hemimegalencephaly (HME), and polymicrogyria (PMG) with megalencephaly, all recently associated with de novo germline or post-zygotic variants that result in activation of the mTOR-PI3K- AKT pathway. Successfully completed, this project will provide a blueprint for best practices in the clinical application of genomics to the care of patients with brain malformations: selecting appropriate diagnostic testing, interpreting variants, and choosing appropriate management.
PROJECT SUMMARY Brain malformations are a diverse group of disorders that can cause intellectual disability, epilepsy, and other neurodevelopmental impacts, with substantial impact on patients, families, and the health care system. To date, mutations in over 1000 different genes have been reported to cause brain malformations. This project brings together a multidisciplinary team of experts to curate the growing body of genetic data (genes and specific variants) related to brain malformations, to help clinicians select appropriate genes for testing and interpret results, en route to establishing a diagnosis and informing care.
|Ormond, Kelly E; Hallquist, Miranda L G; Buchanan, Adam H et al. (2018) Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background. Genet Med :|