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

中枢神经系统先天性畸形疾病基因的系统鉴定

• 批准号: 418099105
• 负责人: Professor Dr. Heiko Reutter
• 金额: --
• 依托单位: Cologne Center for Genomics
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418099105?language=en
• 关键词: Systematic; identification; disease; genes; congenital

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.

中枢神经系统（CNS）的先天性畸形可影响大脑和/或神经管（神经管缺陷，NTD）。CNS畸形表现为孤立的（非综合征性）或非孤立的（综合征性）遗传综合征的一部分。最常见的脑畸形包括胼胝体发育不全、前脑无裂畸形、各种形式的视隔发育不良、无脑回畸形、大脑皮层发育的其他畸形、神经元迁移障碍、颅内囊肿和脂肪瘤、脑膨出、先天性脑积水、各种形式的基亚里畸形和丹迪步行者综合征以及中脑畸形。这些不同的脑畸形可能存在广泛的临床谱。例如，胼胝体的异常可能从胼胝体变薄到部分或完全发育不全。NTD最常见的形式是脊髓脊膜膨出，是尾椎的开放性病变，包含发育不良的脊髓，通常导致缺陷水平以下的神经功能缺失。受影响的患者通常行走能力下降，或需要使用轮椅，肠道和/或膀胱控制很少或没有，需要频繁的手术干预以尽量减少脑积水的影响。同一家族中可能发生不同形式的NTD，这表明存在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核型和染色体微阵列分析后仍未被诊断出来。这是因为许多这些异常都是单基因的，是由大量不同基因或非编码区的大量突变引起的，为了确定先天性CNS畸形的新候选基因，我们将对260例受影响的胎儿进行WES分析。通过这种方法，我们还旨在鉴定其他患有脑畸形的胎儿或患者，这些胎儿或患者携带我们组BAZ 1A、C2 DC 3、CNTN 6、ERMARD、GPR 52、KLHL 15、PLXNA 1、PTPRD、RASD 1、SKA 1、SVIP、TFAP 2 E、TJP 1和UBTD 2先前描述的候选基因突变。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，我们计划系统地筛查与先天性中枢神经系统畸形相关的编码和非编码基因组突变。因此，我们认为，我们计划在50个胎儿/患者病例-父母三人组中进行全基因组测序（WGS）分析，不仅调查外显子组，还调查非编码基因组的致病显性和隐性变异以及拷贝-鉴定先天性CNS畸形的新基因或基因组区域可能为哺乳动物模式形成提供新的见解，并将导致更好地理解分子机制导致人类中枢神经系统发育严重紊乱。高致病率基因的鉴定也将带来新的诊断可能性。