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.