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.
| Dobyns, William B; Aldinger, Kimberly A; Ishak, Gisele E et al. (2018) MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet 103:1009-1021 |
| Brock, Stefanie; Stouffs, Katrien; Scalais, Emmanuel et al. (2018) Tubulinopathies continued: refining the phenotypic spectrum associated with variants in TUBG1. Eur J Hum Genet 26:1132-1142 |
| Di Donato, Nataliya; Timms, Andrew E; Aldinger, Kimberly A et al. (2018) Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genet Med 20:1354-1364 |
| Haldipur, Parthiv; Dang, Derek; Millen, Kathleen J (2018) Embryology. Handb Clin Neurol 154:29-44 |
| Garavelli, Livia; Ivanovski, Ivan; Caraffi, Stefano Giuseppe et al. (2017) Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients. Genet Med 19:691-700 |
| Moore, Cynthia A; Staples, J Erin; Dobyns, William B et al. (2017) Characterizing the Pattern of Anomalies in Congenital Zika Syndrome for Pediatric Clinicians. JAMA Pediatr 171:288-295 |
| Lardelli, Rea M; Schaffer, Ashleigh E; Eggens, Veerle R C et al. (2017) Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet 49:457-464 |
| Di Donato, Nataliya; Chiari, Sara; Mirzaa, Ghayda M et al. (2017) Lissencephaly: Expanded imaging and clinical classification. Am J Med Genet A 173:1473-1488 |
| De Mori, Roberta; Romani, Marta; D'Arrigo, Stefano et al. (2017) Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects. Am J Hum Genet 101:552-563 |
| Brun, Brianna N; Mockler, Shelley R H; Laubscher, Katie M et al. (2017) Comparison of brain MRI findings with language and motor function in the dystroglycanopathies. Neurology 88:623-629 |
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