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

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.

As well as the clinicians and researchers defined in the academic beneficiaries section, the research foreseen in this project will have an important impact on children and families affected by neurogenetic diseases, both in Turkey and beyond. Furthermore, it will impact on the Turkish healthcare and research systems and provide important data for Turkish government policy towards the issues of recessive conditions caused by consanguineous inheritance in the population.

Impact on patients and families
Neurogenetic diseases are a group of severe and chronic childhood disorders affecting the brain, the nervous system and skeletal muscle. Living with these conditions causes a significant welfare and economic burden to affected families and to the country as a whole.
--Improving diagnosis. The majority of patients with these conditions do not have a genetic diagnosis. This makes it more difficult to offer appropriate family counselling to allow reproductive choices and avoidance of future affected pregnancies through pre-implantation genetic diagnosis. By increasing diagnostic rates and discovering new genetic causes of these conditions, we will enable these families to access support appropriate for their conditions.
--Offering treatment. Although curative therapies altering the underlying genetic defect do not exist for these conditions, a number of the conditions have therapies available that can modify the disease course and improve life quality. In the majority of cases it is important to understand the underlying genetic defect in order to offer the correct treatment.
---Paving the way to future therapies. The research carried out in this project has clear translational potential, since understanding pathways and mechanisms can result in identification of new therapeutic targets. The UK partner has a strong translational research track record, including first-in-man trials in rare diseases, and this will ensure the impact of new discoveries from this project.

Impact on national policy for the consanguineous health burden
As shown in more detail in the Case for Support, as many as one in four marriages in Turkey is consanguineous, and government policy to address the health burden of recessive conditions that are more common in this population is a high priority, but needs adequate data on which to base policy. This project will generate the largest comprehensively genetically and phenotypically defined cohort of families affected by neurogenetic disorders of childhood and thus provide a rich body of data for policy planning.

Impact on the Turkish economy
The extensive upskilling of Turkish participants in genomic medicine is a main aim of the project, ensuring its legacy is a lasting benefit for the Turkish healthcare system and economy through new opportunities in the diagnostics and healthcare market. This also has an impact on potential revenue-generating activities for the country in terms of new diagnostic and healthcare services. Data, service, skills and personnel developed in the project may help to set up spin-out diagnostic services and enrich the health care market in Turkey and the wider region. The data obtained may be valuable tools for politicians and economists to plan health care provision targeted for the Turkish population and particularly consanguineous families