Our general goal for this project is to advance our understanding of human developmental disorders that involve the brainstem and cerebellum - brain structures derived from the embryonic midbrain and hindbrain - that affect a minimum of 2.4 per 1000 resident births based on data from the CDC. Importantly, this large class of disorders co-occurs with more common developmental disorders such as autism, mental retardation and some forms of infantile epilepsy, and shares some of the same causes. With this renewal, we propose to expand the scope of our work beyond single phenotypes and genes to focus on delineating the critical phenotype spectra to which the most common MHM belong, and defining the underlying biological networks that are disrupted. To pursue these goals, we will use our large and growing cohort of human subjects to map additional MHM loci using SNP microarrays that provide both high-resolution autozygosity and linkage data in informative families as well as detect critical copy number variants in sporadic subjects. The causative genes will be identified using traditional Sanger or new high-throughput sequencing methods as appropriate abased on size of the critical region. We will use these and other known MHM causative genes to construct and revise model biological networks of genes and proteins, and test these genes and networks in additional patients as a candidate gene or more accurately a candidate network approach. These approaches need to be supported by ongoing active subject recruitment, as studies of comparable disorders such as mental retardation and autism have benefited from even larger numbers of subjects that we have so far collected. We need to use new high- throughput sequencing methods to more efficiently test larger critical regions, and to test entire gene networks rather than individual genes in matched cohorts of subjects. At every step - phenotype analysis, CNV analysis, model network construction and high-throughput sequencing - we will need expanded bioinformatics capabilities. Finally, we need to test the biological function of new genes and networks to support our gene identification studies. We expect that these studies will contribute immediately to more accurate diagnosis and counseling, and over time will lead to development of specific treatments for a subset of these disorders. We further expect that studies of mid-hindbrain development will have broad significance for human developmental disorders generally, providing compelling evidence for a connection between cerebellar development and other classes of developmental disorders such as autism, mental retardation and epilepsy.
Developmental disorders of the brainstem and cerebellum - which are derived from the embryonic midbrain and hindbrain - are a collectively important class of disorders that affect a minimum of 2.4 per 1000 resident births based on data from the CDC. The true frequency is likely much higher. This large class of disorders co-occurs with more common developmental disorders such as autism, mental retardation and some forms of infantile epilepsy, and shares some of the same causes. We propose to find the causes of several different types of brainstem and cerebellar malformations, which will contribute to more accurate diagnosis and counseling in the short term, and to specific treatments for some of these disorders in the long term.
|Aldinger, Kimberly A; Mosca, Stephen J; Tétreault, Martine et al. (2014) Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy. Am J Hum Genet 95:227-34|
|Cacciagli, Pierre; Desvignes, Jean-Pierre; Girard, Nadine et al. (2014) AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome). Eur J Hum Genet 22:363-8|
|Sulakhe, Dinanath; Balasubramanian, Sandhya; Xie, Bingqing et al. (2014) Lynx: a database and knowledge extraction engine for integrative medicine. Nucleic Acids Res 42:D1007-12|
|Mirzaa, Ghayda M; Millen, Kathleen J; Barkovich, A James et al. (2014) The Developmental Brain Disorders Database (DBDB): a curated neurogenetics knowledge base with clinical and research applications. Am J Med Genet A 164A:1503-11|
|Sulakhe, Dinanath; Taylor, Andrew; Balasubramanian, Sandhya et al. (2014) Lynx web services for annotations and systems analysis of multi-gene disorders. Nucleic Acids Res 42:W473-7|
|Cushion, Thomas D; Paciorkowski, Alex R; Pilz, Daniela T et al. (2014) De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy. Am J Hum Genet 94:634-41|
|Tully, Hannah M; Dobyns, William B (2014) Infantile hydrocephalus: a review of epidemiology, classification and causes. Eur J Med Genet 57:359-68|
|Sulakhe, Dinanath; Balasubramanian, Sandhya; Xie, Bingqing et al. (2014) High-throughput translational medicine: challenges and solutions. Adv Exp Med Biol 799:39-67|
|Ishak, Gisele E; Dempsey, Jennifer C; Shaw, Dennis W W et al. (2012) Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity. Brain 135:1370-86|
|Labelle-Dumais, Cassandre; Dilworth, David J; Harrington, Emily P et al. (2011) COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans. PLoS Genet 7:e1002062|
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