Clinical Domain Working Groups

Brain malformations comprise a group of genetic developmental brain disorders that present in childhood with intellectual disability, epilepsy, and other neurologic features, causing substantial morbidity, mortality, and health care costs. We now know that many cases of brain malformation are the result of rare, heritable causes; in other cases, they arise from de novo or somatic mutational events at the gamete or post-zygote stage. In all cases, establishing the correct genomic diagnosis is the cornerstone for proper clinical management.

We have assembled an Expert Panel with deep, diverse expertise in genetic human brain malformations, including clinical phenotyping, neuroimaging, genetics, neurobiology, and bioinformatics. We have included clinical-researchers with both bench and clinical expertise, including colleagues involved in ClinGen to facilitate integration of our findings into the ClinGen infrastructure. Our group represents innovative genomic research in brain malformation genetics, particularly somatic mutation gene discovery and single-cell genomic approaches to understanding the cell of origin of mutations associated with some malformations.

We will review the variants asserted to be associated with brain malformations (HPO:0012443) within the mTOR- PI3K-AKT pathway and systematically curate each variant according to ClinGen standards. We will focus on deep curation of variants in the genes AKT3, PIK3CA, PIK3R2, MTOR, and DEPDC5.

The other family of genes the expert panel will specify will be associated with the Tubulinopathies. The following genes with Definitive gene-disease relationships: TUBA1A, TUBB3, TUBB2B and TUBG1 will be specified by the VCEP as variants in these genes are frequently reported and submitted to ClinVar. The majority of variants in these genes are expected to be of germline nature and present in all tissues without mosaicism.