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.

Public Health Relevance

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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Whittemore, Vicky R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital Boston
United States
Zip Code
Reiff, Rachel E; Ali, Bassam R; Baron, Byron et al. (2014) METTL23, a transcriptional partner of GABPA, is essential for human cognition. Hum Mol Genet 23:3456-66
Cai, Xuyu; Evrony, Gilad D; Lehmann, Hillel S et al. (2014) Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep 8:1280-9
Adachi, Yuko; Mochida, Ganeshwaran; Walsh, Christopher et al. (2014) Posterior fossa in primary microcephaly: relationships between forebrain and mid-hindbrain size in 110 patients. Neuropediatrics 45:93-101
Zhang, Xiaochang; Ling, Jiqiang; Barcia, Giulia et al. (2014) Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am J Hum Genet 94:547-58
Hu, Wen F; Chahrour, Maria H; Walsh, Christopher A (2014) The diverse genetic landscape of neurodevelopmental disorders. Annu Rev Genomics Hum Genet 15:195-213
Di Costanzo, Stefania; Balasubramanian, Anuradha; Pond, Heather L et al. (2014) POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations. Hum Mol Genet 23:5781-92
Willoughby, Brian L; Favero, Marcus; Mochida, Ganeshwaran H et al. (2014) Neuropsychological function in a child with 18p deletion syndrome: a case report. Cogn Behav Neurol 27:160-5
Bae, Byoung-Il; Tietjen, Ian; Atabay, Kutay D et al. (2014) Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning. Science 343:764-8
Jamuar, Saumya S; Lam, Anh-Thu N; Kircher, Martin et al. (2014) Somatic mutations in cerebral cortical malformations. N Engl J Med 371:733-43
Akawi, Nadia A; Canpolat, Fuat E; White, Susan M et al. (2013) Delineation of the clinical, molecular and cellular aspects of novel JAM3 mutations underlying the autosomal recessive hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Hum Mutat 34:498-505

Showing the most recent 10 out of 54 publications