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

在这个项目中，来自土耳其不同地区(伊兹密尔、迪尔巴克尔和马拉蒂亚)的三个儿科神经科将与伊兹密尔的最先进的基因组中心和英国泰恩河畔纽卡斯尔的一个领先的翻译研究中心合作，开展一个尖端的新基因组项目。这项研究将为土耳其人解决一个与健康相关的重要问题：近亲婚姻造成的儿童神经遗传疾病的负担。土耳其四分之一的婚姻是血缘关系(血缘)。亲属因为有共同的祖先而共享部分DNA，在这些共享的区域中，他们也有一些相同的基因缺陷(突变)。因此，与非血缘家庭相比，有血缘关系的家庭中孩子从母亲和父亲那里继承相同缺陷的风险要高得多，这增加了隐性疾病(即父母双方都必须将过错传递给孩子才会患上这种疾病)的可能性。大脑和神经系统中活跃的基因比身体其他任何部位都多。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、肌肉无力、呼吸问题和严重的学习困难。在土耳其，每年有数千名受神经遗传疾病影响的儿童出生在近亲家庭。基因诊断能让家庭避免孩子的进一步患病，在某些情况下还能开出有效的治疗处方，这是很少实现的，因为根本原因很难确定，到目前为止，所需的测试既昂贵又耗时。与逐个查看基因不同，现在可以在一次测试中读取孩子的整个基因密码，并通过将这些信息与普通人群和健康的亲属，特别是父母进行比较来识别缺陷基因。这在血缘关系密切的家庭中尤其有效，因为预计受影响的孩子从父亲和母亲那里继承了相同的缺陷。从近亲家庭获得的信息已经有助于识别致病的基因缺陷，也可能找到导致原发疾病或多或少严重的其他基因。在这个项目中，土耳其的儿科神经科专家将对大约250名患有严重儿童脑部、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那里获取血液和微小皮肤样本。DNA将从血液中提取，并将接受基因组测序，然后进行深入的计算机分析。相关基因中的潜在缺陷将被识别出来，并将被进一步研究，以确定它们的功能，并看看它们是否确实是导致儿童疾病的原因。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基因操作，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。在鱼身上探索这些方面有助于研究开发针对人类这些疾病的有针对性和有效的治疗方法。除了预计将发现至少20个新的致病基因外，我们还将为未来的研究产生和分享有价值的数据，并将培训土耳其的临床和科学工作人员使用这些新技术。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和其他血亲比率较高的移民人口中严重儿童障碍的影响。

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.