Title: New genomic approaches to explore the neurogenetic disease burden of consanguineous marriages in Turkey
Funder: Medical Research Council

Abstract: 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 imm


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL