Brain Malformation Expert Panels for Gene and Variant Curation

PROJECT SUMMARY Brain malformations comprise a group of genetic developmental brain disorders that present in childhood with epilepsy, intellectual, and other neurologic features, causing substantial morbidity, mortality, and health care costs. To date, mutations in hundreds of genes have been linked to

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 an expert panel of clinician-investigators with broad, complementary expertise in brain malformations in the

domains of gene discovery, neurobiology, clinical phenotype, radiographic presentation, and treatment. This panel will survey the literature to curate genes and variants 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. They will work together with the

ClinGen infrastructure and partner with biocurators from the Broad Institute to curate brain malformation genes through the Brain Malformations Gene Curation Expert Panel and variants in these genes through the Brain Malformations Variant Curation Expert Panel. A special focus of this group is the development of rigorous approaches to assess brain

malformations caused by somatic mutations, a molecularly and clinically distinct subgroup of disorders (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) for

which there are potentially important implications for treatment. Having created a blueprint for mosaic variant curation with recently published curation rules, this project will foster best practices in the clinical application of genomics to the care of patients with brain malformations: selecting

appropriate diagnostic testing, interpreting variants, and ultimately choosing appropriate management.