The number of recognized brain malformations and syndromes has grown rapidly during the past several decades, yet relatively few causative genes have been identified, especially for three common malformations that have been associated with numerous cytogenetically visible chromosome deletions and duplications, and that often occur together: agenesis of the corpus callosum (ACC), cerebellar vermis hypoplasia (CVH) including Dandy-Walker malformation (DWM), and polymicrogyria (PMG). We propose to perform high-resolution array comparative genome hybridization (aCGH), emerging technology able to detect small copy number variants (CNV), in 700 probands with one or more of these three malformations. Our central hypothesis states that more than 10% of patients with ACC, CVH or PMG will have de novo CNV below the resolution of routine cytogenetic analysis, but detectable by current array platforms. We therefore expect to identify 70-100 patients with small CNV. We will distinguish CNV found in normal individuals from potentially disease-associated changes, and will confirm CNV using fluorescence in situ hybridization (FISH) and microsatellite (STRP) analysis. We will give highest priority to CNV that are de novo and involve 2 or more BACs, and secondary priority to familial and smaller CNV excluding known polymorphisms. After that, we will evaluate and rank candidate genes in the critical regions using information from public databases and our own expression studies, and perform mutation analysis of the best candidate genes from well-defined critical regions by sequencing in a large panel of subjects with phenotypes that match the phenotypes of the patients whose CNV define the critical regions. Here, we will use more refined criteria to supplement our clinical classification, such as the developmental level and presence of epilepsy or other birth defects. Any abnormalities found will be analyzed using existing data regarding polymorphisms (i.e. dbSNP), cross-species comparisons, and functional assays appropriate for the specific sequence change. We expect our focus on small chromosome imbalances to efficiently lead to discovery of new genes that cause these three focus malformations. These discoveries will lead directly to improved care for affected children and families consisting of more accurate diagnosis and outcome counseling, which will include specific diagnostic testing, as well as improved genetic counseling.

Public Health Relevance

The work proposed in this grant will lead to lead to the discovery of many of the genes that cause of birth defects of the brain and related - but often less severe - developmental disorders. These results will prove immediately helpful in providing better information regarding diagnosis and prognosis to the families of affected children, and will also lead to better understanding of the underlying biology and in some cases to more effective treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (05))
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Seattle Children's Hospital
United States
Zip Code
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
Jordan, Valerie K; Fregeau, Brieana; Ge, Xiaoyan et al. (2018) Genotype-phenotype correlations in individuals with pathogenic RERE variants. Hum Mutat 39:666-675
Marco, Elysa Jill; Aitken, Anne Brandes; Nair, Vishnu Prakas et al. (2018) Burden of de novo mutations and inherited rare single nucleotide variants in children with sensory processing dysfunction. BMC Med Genomics 11:50
Gstrein, Thomas; Edwards, Andrew; P?istoupilov√°, Anna et al. (2018) Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans. Nat Neurosci 21:207-217
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
Tripathy, Ratna; Leca, Ines; van Dijk, Tessa et al. (2018) Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations. Neuron :
Marsh, Ashley P L; Edwards, Timothy J; Galea, Charles et al. (2018) DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome. Hum Mutat 39:23-39
Marsh, Ashley P L; Heron, Delphine; Edwards, Timothy J et al. (2017) Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance. Nat Genet 49:511-514
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

Showing the most recent 10 out of 71 publications