Developmental brain malformations are at the core of significant neurological diseases affecting many families in the United States and around the world. Epilepsy, specific learning deficits and intellectual disabilities, cerebral palsy, and abnormalities of brain size can often be attributed to pathological malformations of the cerebral cortex. Although symptoms such as epilepsy and intellectual disabilities may appear broadly in the population for any number of reasons, our focus on those cases associated with cortical malformations highlights individual developmental pathways likely represented by innumerable and rare Mendelian alleles. Our lab has uncovered dozens of genes associated with these conditions, and we are beginning to dissect the mechanisms underlying early cortical development. However, we know many more genes are yet to be discovered and these currently unidentified genes will provide even more important insight into brain development and function. The goal of our research is to identify novel genetic factors that result in abnormal human cerebral cortical development. This is achieved through 1] ascertaining families with congenital brain malformations, presumably due to inherited factors, and categorizing conditions using neuroimaging data, 2] identifying the genes that harbor mutations that cause the malformations, and 3] describing the function of these genes. We focus on the Middle East for ascertainment of families, where the prevalence of intra-familial marriage and large family size enriches this population for rare Mendelian disorders and offers significant power to distinguish gene targets through homozygosity mapping. The causative mutations are then identified using whole exome sequencing. The mutated gene is further characterized in cell lines, zebrafish, and mouse models in order to elucidate its function. The discovery of new genes, which when mutated result in abnormal brain development, impacts human health in several ways. These discoveries 1] provide insight into classification and diagnosis of these often devastating conditions that can be quickly translated to clinical practice, 2] permit improved genetic counseling and testing for concerned families, and 3] offer an enhanced understanding of the underlying molecular processes of the developing human brain which can inform the conception of potential future therapies or interventions. These treatments may apply not only to our specific, often under-served, patient populations, but also more broadly to numerous patients impacted by the relatively common symptoms of seizures and intellectual and motor impairments. Hence, our research works to reduce the burden of neurologic disease on our human society and does so with important short and long-term implications.
Human brain development is a complicated and poorly understood process and when something interferes with it, devastating medical problems can result. Our goal is to better understand the normal process of brain formation and growth, which we do by studying patients with severe neurological symptoms and abnormal brain structure. These individuals provide examples of when something has gone wrong with the normal process and by trying to understand exactly what happened, we can gain insight into the normal pathways of brain development while finding ways of identifying and treating patients affected by these significant neurological conditions.
|Coulter, Michael E; Dorobantu, Cristina M; Lodewijk, Gerrald A et al. (2018) The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles. Cell Rep 24:973-986.e8
|Rodin, Rachel E; Walsh, Christopher A (2018) Somatic Mutation in Pediatric Neurological Diseases. Pediatr Neurol 87:20-22
|Walsh, Christopher A (2018) Rainer W. Guillery and the genetic analysis of brain development. Eur J Neurosci :
|Johnson, Matthew B; Sun, Xingshen; Kodani, Andrew et al. (2018) Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size. Nature 556:370-375
|Stouffs, K; Stergachis, A B; Vanderhasselt, T et al. (2018) Expanding the clinical spectrum of biallelic ZNF335 variants. Clin Genet 94:246-251
|Smith, Richard S; Kenny, Connor J; Ganesh, Vijay et al. (2018) Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development. Neuron 99:905-913.e7
|Chen, Ming Hui; Choudhury, Sangita; Hirata, Mami et al. (2018) Thoracic aortic aneurysm in patients with loss of function Filamin A mutations: Clinical characterization, genetics, and recommendations. Am J Med Genet A 176:337-350
|Marsh, Ashley P L; Edwards, Timothy J; Galea, Charles et al. (2018) DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome. Hum Mutat 39:23-39
|Lakhani, Shenela; Doan, Ryan; Almureikhi, Mariam et al. (2017) Identification of a novel CNTNAP1 mutation causing arthrogryposis multiplex congenita with cerebral and cerebellar atrophy. Eur J Med Genet 60:245-249
|Evrony, Gilad D; Cordero, Dwight R; Shen, Jun et al. (2017) Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome. Genome Res 27:1323-1335
Showing the most recent 10 out of 98 publications