Genetics of human developmental brain disorders

Developmental brain malformations are at the core of significant neurological diseases affecting many families in the United States and around the world. It is known that epilepsy, specific learning deficits and intellectual disability, cerebral palsy, and abnormalities of brain volume can be attributed in many cases to pathological malformations of the cerebral cortex. Although these consequences, such as epilepsy and intellectual disability, might appear broadly in the population as due to complex traits, this study's focus on those associated with cortical malformations highlights individual developmental pathways likely represented by innumerable and rare Mendelian alleles. Research has thus far uncovered dozens of genes responsible for these conditions and dissected the mechanisms underlying early cortical development in animals. However, this progress represents only the dawn of understanding the complex genetic network and neuronal architecture of the uniquely human cerebral cortex.

The overall goal of this study is to define the genetic bases of human cerebral cortical development. This is accomplished through (1) the ascertainment of families with disorders of human brain development and malformation, (2) categorizing these using medical, physical and neuroimaging data, and (3) mapping and identifying the gene causing the disorder of cortical development, which can then be investigated for its normal expression and function, and role in human disease.

• Study Design:
  • Cross-Sectional
• Study Type:
  • Probands
  • Mendelian
  • Family
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 96
• Subject Sample Telemetry Report (SSTR)

• PubMed

Inclusion Criteria: Persons having a brain malformation (i.e.: microcephaly, heterotopias, polymicrogyria, or lissencephaly), familial intellectual disability, and/or epilepsy. Unaffected family members of enrolled probands may also be included. Males and females of any age, race or ethnicity are included.

Exclusion Criteria: Persons with a probable non-genetic cause already identified for their brain malformation or intellectual disability, and those without a brain malformation or intellectual disability.

The first data release of this study consists of WES data from 58 subjects with a variety of brain malformations from mostly consanguineous families. The second data release provides WES, WGS, targeted sequencing, RNA sequencing, as well as Illumina and Affymetrix microarray genotyping data from a single First Nations population and controls with microcephaly-micromelia syndrome (MMS).

• Primary Phenotype: Microcephaly
• Polymicrogyria
• Polymicrogyria, bilateral perisylvian
• Pachygyria, frontotemporal
• Bilateral periventricular nodular heterotopia
• Familial Nodular Heterotopia
• Cobblestone lissencephaly
• Cerebellar Ataxia
• Agenesis of corpus callosum
• Epilepsy, Familial Tonic-Clonic
• Intellectual disability
• Abnormalities, Congenital, Nervous System
• Dysmorphism Multiple Structural Anomalies
• Microcephaly-Micromelia Syndrome

• ASNS
• CA2
• DHCR24
• DIAPH1
• GRID2
• VLDLR
• KATNB1
• DEAF1
• ARFGEF2
• EXOC7
• more ...

• Principal Investigator
  • Christopher A. Walsh. Boston Children's Hospital, Division of Genetics and Genomics, Boston, MA, USA.
• Funding Sources
  • U54 HG003067. National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD, USA.
  • R01 NS035129. National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, USA.
  • Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Dubai Harvard Foundation for Medical Research Collaborative Research Center Award.
  • NPRP 5-175-3-051. Qatar National Research Fund.
  • R21TW008223. Fogarty International Center (FIC), National Institutes of Health, Bethesda, MD, USA.
  • Boston Children's Hospital, Manton Center for Orphan Disease Research, Boston, MA, USA.