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

先天性中枢神经系统(CNS)畸形会影响大脑和/或神经管(神经管缺陷，NTDS)。作为遗传综合征的一部分，中枢神经系统畸形表现为孤立的(非综合征)或非孤立的(综合征)。最常见的脑畸形包括穹隆发育不全、全前脑、各种形式的隔-视神经发育不良、无脑、大脑皮层发育的其他畸形、神经元移行障碍、颅内囊肿和脂肪瘤、脑膨出、先天性脑积水、各种形式的Chiari畸形和Dandy Walker综合征以及脑裂畸形。这些不同的脑畸形可能呈现出广泛的临床谱系。最常见的NTDS类型为脊髓脊膜膨出，是位于脊椎尾部的开放性病变，含有发育不良的脊髓，常导致缺损区以下的神经功能缺失。受影响的患者通常行走能力降低，或需要使用轮椅，很少或根本没有肠道和/或膀胱控制，需要经常手术干预，以将脑积水的影响降至最低。不同形式的NTDS可以出现在同一个家庭中，这表明共同的潜在遗传原因。即使在今天，大多数先天性中枢神经系统畸形患者在正常的核型和染色体微阵列分析后仍未被诊断出来。这是因为这些异常中的许多是单基因的，由许多不同的基因或非编码区的大量突变引起。为了确定先天性中枢神经系统畸形的新候选基因，我们将对260个受影响的胎儿进行WES分析。通过这种方法，我们还旨在识别更多的胎儿或脑畸形患者，这些胎儿或患者携带我们小组先前描述的候选基因BAZ1A、C2DC3、CNTN6、ERMARD、GPR52、KLHL15、PLXNA1、PTPRD、RASD1、SKA1、SVIP、TFAP2E、TJP1和UBTD2的突变。由于对疑似遗传性疾病个体基因组编码部分的测序只能识别25%-50%的疾病相关突变，我们计划系统地筛选与先天性中枢神经系统畸形相关的编码和非编码基因组中的突变。因此，我们计划对50个胎儿/患者病例-父母三人组进行全基因组测序，不仅调查外显性和非编码基因组中的显性和隐性致病变异以及拷贝数变异。识别先天性中枢神经系统畸形的新基因或基因组区域可能为哺乳动物模式的形成提供新的见解，并将有助于更好地理解导致人类中枢神经系统发育严重障碍的分子机制。高外显性致病基因的识别也将带来新的诊断可能性。

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.