Our principal studies focus on genes that regulate the development and function of the human cerebral cortex. Mutations in these genes cause autism and epilepsy, as well as intellectual disability and other learning disorders. These genes are not only vital to the normal development of the cortex, but many also appear to have been altered by evolution, endowing the brain with the unique attributes that underlie human cognitive abilities.
Double cortex syndrome.
In patients with the brain developmental disorder X-linked lissencephaly, or double cortex syndrome, a second layer of cells (cortex) is formed in the interior of the brain (see pink, denoted by arrows). In many cases, this results from the functional alteration or loss of the gene doublecortin (DCX), which is critical for directing nerve cells to the outer layer of the brain. (Click to enlarge.)
We are also investigating the underlying causes of these neurological diseases:
Autism is a highly heritable illness, yet to date, we have only uncovered genetic causes for 5 to 15 percent of cases. We are trying to attack this problem by uncovering new autism genes. To do this, we're studying families of children affected by autism who have evidence of shared ancestry--either recently via intermarriage between cousins, or remotely via a distant, common ancestor--and using whole genome sequencing to uncover mutations associated with the disease.
At right, an MRI image of the brain of a child with microcephaly (nearly 3 years of age). At left, an MRI image of the brain of a normal child of approximately the same age. (Click to enlarge.)
Microcephaly is a rare condition in which the brain fails to achieve normal growth. Our laboratory has been interested in the genetic causes of microcephaly, since the genes responsible are likely to be involved in key steps of neurogenesis and brain development. Over the past several years, we have enrolled more than 200 families with genetic forms of microcephaly, and have identified several novel microcephaly genes including ASPM, ARFGEF2, CDK5RAP2, PNKP and TRAPPC9.
To read more about our work, click here to visit our lab website.
About Christopher Walsh
Chris Walsh is Chief of the Division of Genetics at Boston Children's Hospital and the Bullard Professor of Neurology at Harvard Medical School. He is also an Investigator of the Howard Hughes Medical Institute. He received his B.S. at Bucknell University in chemistry and his MD/PhD in neurobiology at the University of Chicago. He completed his internship in medicine, residency in neurology and fellowship at Massachusetts General Hospital and Harvard Medical School.
His research has been recognized by multiple honors, including the Derek Denny-Brown Award, Dreifuss-Penry Epilepsy Award, Jacob Javits Distinguished Investigator Award, Epilepsy Research Award and the Jacoby Research Award. He is a fellow of the American Association for the Advancement of Science.
- Chahrour MH et al. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet.2012;8(4):e1002635.
- Poduri A et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 2012 Apr 12; 74(1):41-8.
- Alkuraya FS et al. Human mutations in NDE1 cause extreme microcephaly with lissencephaly. Am J Hum Genet. 2011 Apr 29.
- Lehtinen et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 2011 Mar 10;69(5):893-905.
- Kim S et al. The apical complex couples cell fate and cell survival to cerebral cortical development. Neuron 2010 Apr 15; 66(1):69-84.
- Shen J et al. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nature Genetics 2010 March; 42(3):245-9.
- Walsh CA et al. Autism and brain development. Cell 2008 Oct 31; 135(3):396-400.
- Morrow EM et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 2008 Jul 11; 321(5886): 218-23.
- Sun T et al. Early asymmetry of gene transcription between embryonic human left and right cerebral cortex. Science 2005; 308(5729):1794-8.
For a complete list of Chris Walsh's publications in PubMed, click here.