Oligogenic inheritance of known ALS genes was not prominent in the Turkish C9orf72-positive cases. Common current themes in ALS, like oligogenic inheritance and possible genetic modifiers are addressed in families with incomplete penetrance and in C9orf72 expansion carriers. Application of whole exome sequencing (WES) in dominant and recessive Turkish pedigrees presenting with ALS or non-als motor neuron diseases (MNDs), revealed distinct rare or novel mutations in 20 out of 39 families and enabled differential diagnosis in cases with atypical ALS features. C9orf72 hexanucleotide repeat expansion was further detected in 3% of apparently sporadic patients. Conventional screening of the most common ALS genes (C9orf72, SOD1, TARDBP and FUS) in patients with a family history of disease, explained the disease cause in only 33%, pointing towards marked locus heterogeneity within the population. Consanguinity is calculated as 25% among familial and 17% in sporadic cases. Familial ALS account for 22% of our cases (159/722) and 563 cases were classified as sporadic (78%).
In this thesis, we investigated the complex genetics of ALS in the ethnically heterogeneous yet inbred Turkish population. The last decade has proven that the condition called ALS is both clinically and genetically heterogenous, and that the genetic component in 90% of the cases that are considered as sporadic, might be stronger than expected. With an incidence of two and a prevalence of four in /year, it is the third most common NDD after Alzheimer s and Parkinson s diseases. Last but not least, I heartily would like to express my appreciation and admiration to my parents Ece and Cenk İskender for their endless support and unconditional love and genuinely thank my husband Can Tunca for collaborating with me in the greatest experiment ever, life.ĥ v ABSTRACT THE MOLECULAR LANDSCAPE OF ALS IN TURKEY: A MULTIFACETED APPROACH TO THE COMPLEX GENETICS OF ALS Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease (NDD), characterized by degeneration of both upper and lower motor neurons leading to muscle wasting. I am also especially grateful to Cemre for her excellent assistance in all experiments. Atay Vural for sharing his thoughts on data presentation. I further thank Tuncay for his help in bioinformatic data analysis and Dr. I extend my thanks to Suna for all our creative accomplishments and Fulya for supporting me through my first steps in bioinformatics. I deeply thank all current and former NDAL members, for a truly fruitful working environment and for their sincere friendship that will last for many more years. I respectfully acknowledge the Suna and İnan Kıraç Foundation for financially supporting me and my research. I humbly am grateful to all patients and family members for their cooperation and would like to specially offer my thanks to the esteemed clinicians throughout Turkey who have been collaborating with us. Öznur Taştan for devoting their time to evaluate my thesis. I thank her for offering endless opportunities and for sharing her scientific and personal experiences. Nazlı Başak for her invaluable guidance, support and strong encouragement throughout this thesis.
Öznur Taştan DATE OF APPROVAL:ģ iii To all our patients and their families.Ĥ iv ACKNOWLEDGEMENTS I express my deepest gratitude to my supervisor Prof. 1 THE MOLECULAR LANDSCAPE OF ALS IN TURKEY: A MULTIFACETED APPROACH TO THE COMPLEX GENETICS OF ALS by Ceren Tunca B.S., Biological Sciences and Bioengineering, Sabancı University, 2010 M.S., Molecular Biology and Genetics, Boğaziçi University, 2013 Submitted to the Institute for Graduate Studies in Science and Engineering in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Program in Molecular Biology and Genetics Boğaziçi University 2018Ģ ii THE MOLECULAR LANDSCAPE OF ALS IN TURKEY: A MULTIFACETED APPROACH TO THE COMPLEX GENETICS OF ALS APPROVED BY: Prof.
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