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、迪亚巴克尔、马拉提亚）的三个儿科神经内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）的一个领先的转化研究中心合作，共同开展一个尖端的新基因组项目。该研究将解决土耳其人口的一个重要健康问题：近亲婚姻儿童的神经遗传疾病负担。在土耳其，四分之一的婚姻是血亲婚姻（近亲婚姻）。由于他们有共同的祖先，亲戚之间的部分DNA是相同的，在这些共同的区域，他们也有一些相同的基因缺陷（突变）。因此，与非近亲家庭相比，近亲家庭的孩子从母亲和父亲那里继承相同缺陷的风险要高得多，从而增加了隐性疾病的可能性（父母双方必须将缺陷遗传给孩子才能患病）。大脑和神经系统中活跃的基因比身体其他任何部位都要多。这些基因的隐性缺陷往往导致严重的儿童疾病，造成早期死亡或严重残疾，包括癫痫、肌肉无力、呼吸问题和严重的学习困难。在土耳其，每年有数千名患有神经遗传疾病的儿童出生在近亲家庭中。由于难以查明根本原因，而且迄今为止所需的检测既昂贵又耗时，因此很少能进行基因诊断，以使家庭避免让孩子进一步受到影响，并在某些情况下允许开出有效的治疗处方。现在可以通过一次测试读取儿童的整个遗传密码（整个基因组），而不是一个一个地查看基因，并通过将这些信息与一般人群和健康亲属，特别是父母的信息进行比较，识别出有缺陷的基因。这在近亲家庭尤其有效，因为受影响的孩子可能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确定致病的遗传缺陷，也可能使发现使原发疾病或多或少严重的其他基因成为可能。在这个项目中，土耳其的儿科神经专家将对大约250名患有严重儿童脑、神经系统或肌肉疾病的儿童进行详细的临床调查，并从这些儿童以及他们未受影响的父母和受影响或未受影响的兄弟姐妹身上获取血液和微小的皮肤样本。将从血液中提取DNA，并进行基因组测序，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，并确定它们是否确实是儿童病情的原因。这项科学工作将由纽卡斯尔和伊兹密尔的科学家进行，包括使用干细胞技术将皮肤细胞转化为神经细胞，以及使用基因操作来改变斑马鱼胚胎的基因，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，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。除了预期发现至少20种新的致病基因外，我们还将为今后的研究产生和分享有价值的数据，并将在这些新技术方面培训土耳其的临床和科学工作人员。获得的信息也将有助于未来的土耳其基因组计划，并有助于了解亲属关系对其他国家移民人口和其他高亲属率人口的严重儿童疾病的影响。

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.