New genomic approaches to explore the neurogenetic disease burden of consanguineous marriages in Turkey

新的基因组方法探索土耳其近亲结婚的神经遗传疾病负担

• 批准号: MR/N027302/1
• 负责人: Rita Horvath
• 金额: $ 32.3万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN027302%2F1
• 关键词: New; genomic; approaches; explore; neurogenetic

In this project three paediatric neurology departments from different parts of Turkey (Izmir, Diyrbakir, Malatya) will work together with the state-of-the-art genome centre in Izmir and a leading translational research centre in Newcastle upon Tyne (UK) in a cutting-edge new genome project. The research will address an important health-related issue for the Turkish population: the burden of neurogenetic disorders in children from consanguineous marriages.One in four marriages in Turkey is between blood relations (consanguineous). Relatives share parts of their DNA because of their common ancestry, and in these shared regions they also share some of the same genetic faults (mutations). The risk that a child inherits the same fault from both mother and father is therefore significantly higher in consanguineous families as compared to non-consanguineous families, increasing the likelihood of recessive disorders (in which both parents have to pass on a fault for the child to get the disease).More genes are active in the brain and nervous system than in any other part of the body. Recessive defects in these genes often lead to severe childhood disorders causing early death or severe disability including seizures, muscle weakness, breathing problems and severe learning difficulties. Thousands of children affected by neurogenetic conditions are born every year in Turkey in consanguineous families. A genetic diagnosis that would allow families to avoid having further affected children and in some cases allow effective treatment to be prescribed is rarely achieved because the underlying causes are difficult to pinpoint and the tests required have until now been expensive and time-consuming.Rather than looking at genes one by one, it has now become possible to read the entire genetic code of a child (the whole genome) in a single test and identify faulty genes by comparing this information with the general population and healthy relatives, in particular the parents. This is especially effective in consanguineous families, as the affected child is expected to have inherited an identical fault from both father and mother. Information obtained from consanguineous families has already been helpful in the identification of disease-causing genetic faults and might also make it possible to find other genes that make the primary disease more or less severe. In this project, expert paediatric neurologists in Turkey will carry out detailed clinical investigations of around 250 children with severe childhood disorders of the brain, nervous system or muscle and obtain blood and tiny skin samples from these children as well as their unaffected parents and affected or unaffected siblings. DNA will be extracted from the blood and will undergo genome sequencing followed by in-depth computer analysis. Potential faults in relevant genes will be identified and will be further explored to establish their function and see whether they are indeed the cause of the child's condition. This scientific work will be carried out by scientists in Newcastle and Izmir and involves the use of stem cell technology to transform skin cells into nerve cells, as well as genetic manipulation to change the genes of zebrafish embryos to recreate the problem seen in the child and help understand the function of the gene in the nervous system. Exploring these aspects in fish allows research towards the development of targeted and effective treatments for these diseases in humans. In addition to the expected discovery of at least 20 new disease-causing genes, we will also generate and share valuable data for future research, and will train the clinical and scientific workforce in Turkey in these new techniques. The information obtained will also contribute to future Turkish genome projects, and help understand the impact of consanguinity on severe childhood disorders in immigrant populations in other countries and other populations with high consanguinity rates.

在该项目中，来自土耳其不同地区（伊兹密尔、迪亚巴克尔、马拉蒂亚）的三个儿科神经科将与伊兹密尔最先进的基因组中心和泰恩河畔纽卡斯尔（英国）领先的转化研究中心合作，开展一项尖端的新基因组项目。这项研究将解决土耳其人口的一个重要健康问题：近亲婚姻子女的神经遗传疾病负担，土耳其四分之一的婚姻是血亲（近亲）之间的婚姻。由于他们共同的祖先，亲戚们共享部分DNA，在这些共享区域中，他们也共享一些相同的遗传缺陷（突变）。因此，与非血亲家庭相比，血亲家庭中的孩子从父母那里继承相同缺陷的风险明显更高，从而增加了隐性疾病（父母双方都必须将缺陷传给孩子才能患病）的可能性。大脑和神经系统中活跃的基因比身体任何其他部位都多。这些基因的隐性缺陷通常会导致严重的儿童疾病，导致过早死亡或严重残疾，包括癫痫发作、肌肉无力、呼吸问题和严重的学习困难。土耳其每年有数千名患有神经遗传疾病的儿童出生在近亲家庭。基因诊断可以使家庭避免进一步影响儿童，并在某些情况下可以提供有效的治疗，但这种诊断很少实现，因为根本原因难以查明，而且所需的测试迄今为止既昂贵又耗时。现在已经可以在一次测试中读取儿童的整个遗传密码（整个基因组），并通过将这一信息与一般人口和健康亲属，特别是父母进行比较，来确定有缺陷的基因。这在近亲家庭中特别有效，因为受影响的儿童被认为从父母双方继承了相同的过错。从近亲家庭中获得的信息已经有助于确定致病的遗传缺陷，也可能使人们有可能找到使原发性疾病或多或少严重的其他基因。在该项目中，土耳其的儿科神经科专家将对约250名患有严重儿童期大脑、神经系统或肌肉疾病的儿童进行详细的临床调查，并从这些儿童及其未受影响的父母和受影响或未受影响的兄弟姐妹中获取血液和微小皮肤样本。DNA将从血液中提取，并将进行基因组测序，然后进行深入的计算机分析。相关基因的潜在缺陷将被识别，并将进一步探索，以确定它们的功能，看看它们是否确实是孩子病情的原因。这项科学工作将由纽卡斯尔和伊兹密尔的科学家进行，涉及使用干细胞技术将皮肤细胞转化为神经细胞，以及改变斑马鱼胚胎基因的遗传操作，以重现在儿童身上看到的问题，并帮助了解基因在神经系统中的功能。在鱼类中探索这些方面可以研究开发针对人类这些疾病的靶向和有效治疗方法。除了预计发现至少20种新的致病基因外，我们还将为未来的研究提供和分享有价值的数据，并将在土耳其培训这些新技术的临床和科学工作人员。所获得的信息还将有助于未来的土耳其基因组项目，并有助于了解血缘关系对其他国家移民人口和其他高血缘关系人口中严重儿童疾病的影响。

项目成果

Correction: Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.

更正：继发于新型 CHKB 突变的巨圆锥型先天性肌营养不良症类似于非典型 Rett 综合征。

• DOI: 10.1038/s10038-021-00920-2
• 发表时间: 2021
• 期刊: Journal of human genetics
• 影响因子: 3.5
• 作者: Bardhan M

Mitochondrial and nuclear disease panel (Mito-aND-Panel): Combined sequencing of mitochondrial and nuclear DNA by a cost-effective and sensitive NGS-based method.

• DOI: 10.1002/mgg3.500
• 发表时间: 2018-11
• 期刊: Molecular genetics & genomic medicine
• 影响因子: 2
• 作者: Abicht A;Scharf F;Kleinle S;Schön U;Holinski-Feder E;Horvath R;Benet-Pagès A;Diebold I
• 通讯作者: Diebold I

Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.

• DOI: 10.1212/wnl.0000000000005566
• 发表时间: 2018-05-22
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Bansagi B;Phan V;Baker MR;O'Sullivan J;Jennings MJ;Whittaker RG;Müller JS;Duff J;Griffin H;Miller JAL;Gorman GS;Lochmüller H;Chinnery PF;Roos A;Swan LE;Horvath R
• 通讯作者: Horvath R

Genetic heterogeneity of motor neuropathies.

• DOI: 10.1212/wnl.0000000000003772
• 发表时间: 2017-03-28
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Bansagi B;Griffin H;Whittaker RG;Antoniadi T;Evangelista T;Miller J;Greenslade M;Forester N;Duff J;Bradshaw A;Kleinle S;Boczonadi V;Steele H;Ramesh V;Franko E;Pyle A;Lochmüller H;Chinnery PF;Horvath R
• 通讯作者: Horvath R

Phenotypic convergence of Menkes and Wilson disease.

• DOI: 10.1212/nxg.0000000000000119
• 发表时间: 2016-12
• 期刊: Neurology. Genetics
• 作者: Bansagi B;Lewis-Smith D;Pal E;Duff J;Griffin H;Pyle A;Müller JS;Rudas G;Aranyi Z;Lochmüller H;Chinnery PF;Horvath R
• 通讯作者: Horvath R