Systematic identification of disease genes for congenital malformations of the central nervous system

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Congenital malformations of the central nervous system (CNS) can affect the brain and/or the neural tube (neural tube defects, NTDs). CNS malformations present isolated (non-syndromic) or non-isolated (syndromic) as part of a genetic syndrome. The most common brain malformations include agenesis of the corpus callosum, holoprosencephaly, various forms of septo-optic dysplasia, lissencephaly, other malformations of cerebral cortical development, neuronal migration disorders, intacranial cysts and lipomas, encephaloceles, congenital hydrocephalus, various forms of Chiari malformation and Dandy Walker syndrome, and schizencephaly. These various brain malformations might present with a broad clinical spectrum. For example, anomalies of the corpus callosum might range from thinning to partial or complete agenesis of corpus callosum.The most common form of NTDs, myelomeningocele, is an open lesion in the caudal spine and contains dysplastic spinal cord, often resulting in a lack of neural function below the level of the defect. Affected patients usually have reduced ability to walk, or need the use of a wheelchair, have little or no bowel and/or bladder control, and require frequent surgical interventions to minimize the effects of hydrocephalus. Different forms of NTDs can occur within the same family, suggesting a common underlying genetic cause.Even today, most patients with congenital CNS malformations remain undiagnosed following a normal karyotype and chromosomal microarray analysis. This is due to the fact that many of these abnormalities are monogenic, caused by numerous mutations in a multitude of different genes or non-coding regions.In order to identify novel candidate genes for congenital CNS malformations we will perform WES analysis in 260 affected fetuses. With this approach, we also aim to identify additional fetuses or patients with brain malformations, carrying mutations in previously described candidate genes by our group BAZ1A, C2DC3, CNTN6, ERMARD, GPR52, KLHL15, PLXNA1, PTPRD, RASD1, SKA1, SVIP, TFAP2E, TJP1, and UBTD2. Because sequencing of the coding part of the genome of individuals with a suspected genetic disorder only identifies 25-50% of the disease-associated mutations we plan to systematically screen for mutations in the coding and non-coding genome in association with congenital CNS malformations. Hence, we plan to perform whole-genome sequencing (WGS) analysis in 50 fetal/patient case-parent trios to not only survey the exome but also the non-coding genome for causative dominant and recessive variants as well as copy-number variations.The identification of new genes or genomi regions for congenital CNS malformations may provide new insights into mammalian pattern formation and will lead to a better understanding of molecular mechanisms responsible for the grossly disturbed development of the human CNS. The identification of high-penetrance causative genes will also lead to new diagnostic possibilities.