A. Nazlı Başak, Ph.D.
A. Nazlı Başak, earned her BS degree from the University of Göttingen, Germany and completed her MSc and PhD studies in molecular biology and genetics at Max Planck Institute or Experimental Medicine in Göttingen, under the supervision of Prof. Friedrich Cramer. After three years of postdoctoral fellowhip and five years as research associate at the same institute, she returned in 1985 to Istanbul, Boğaziçi University, and was promoted to an associate professor of molecular biology and genetics in 1986 and to a full professor in 1991.
Dr. Başak’s career at Boğaziçi University started with the establishment of DNA techniques used in the early detection and prevention of hereditary blood disorders. She was instrumental in the establishment of a fully equipped molecular biology and genetics laboratory for the first time in Turkey. Her research laboratory at Boğaziçi University, in collaboration with the Turkish Ministry of Health and associated clinicians, played a major role in the introduction and implication of a comprehensive nation-wide prevention program for the early diagnosis and prenatal detection of thalassemias and abnormal hemoglobins, based on DNA analysis, in Turkey.
In the late nineties Nazli Başak’s research interest shifted from monogenic blood diseases towards complex brain disorders. Dr. Başak’s current research agenda focuses on rare neurological diseases and multifactorial disease genetics. With her interest in mechanisms giving rise to neurodegenerative processes and a special focus on ALS and motor neuron diseases, she was appointed in 2005 as the director of NDAL (Neurodegeneration Research Laboratory), established by Suna and İnan Kıraç Foundation at Boğaziçi University. NDAL from its beginning has been involved in several national and international collaborations, including two multicentered European projects, and soon attained a unique position as a center of excellence for neurodegenerative disease research and molecular diagnosis in Turkey.
Currently NDAL is the Turkish partner of Project MinE, in the framework of which 900 Turkish samples from ALS patients and healthy controls have been genome-sequenced. Another multinational project supported by the Wellcome Trust, concerns genetic modifiers in repeat expansion disorders. The collaboration aims to unravel the genes and their action mechanisms in modifying disease phenotypes and onset ages in ataxias and related movement disorders.
The translocation of NDAL in 2018 to Koç University Medical School (KUTTAM) is of groundbreaking importance, since a tight collaboration between bench scientists and clinicians has never been as crucial as it is in the genome era, fueled by advances in NGS technologies. With its wealth of neurodegenerative disease samples and patient data, with its international collaborations and large-scale projects and with its well-trained team, KUTTAM-NDAL aims to bridge the gap between basic and translational science. The lab has recently joined several multicenter consortia, which have the common goal of unraveling novel disease genes in neurodegenerative diseases, understanding pathogenic mechanisms and ultimately paving the ways for therapies. In addition to being one of the leading contributors to Project MinE in terms of sample sizes, the laboratory is part of the NGS ataxia consortium, based on the EU consortium PREPARE and also represents Turkey in the Rostock International Parkinson’s Disease Study (ROPAD), focusing on Parkinson’s disease genetics.
Considering the application of human genome variation in precision medicine, a Turkish Variome database is being developed in collaboration with Bilkent University in Ankara by aggregating the WES and WGS data of both centers. This comprehensive catalogue, the first high-resolution genetic structure specific to the Turkish population, will not only improve the power of molecular diagnosis by classifying pathogenicity of rare variants when combined with clinical information, but it will also be a valuable resource for disease gene discovery.
The Complex Genetics of Motor Neurone Diseases in Turkey
Turkey is a large country with a young population. In contrast to European countries in which population sizes have steadily been decreasing in the last 50 years, Turkey is still dynamic with a high birth rate and traditionally large kindreds, consisting of several living generations and an impressive number of offspring. Since close consanguineous marriages are still part of the Turkish culture, the number of recessive Mendelian diseases is in excess of what is expected. With its wealthy historical background and unique geographical location, bridging three continents, the Turkish peninsula is a rich genetic pool with a high ethnic heterogeneity.
This study compiles the results of twenty years of molecular analyses in 1200 Turkish ALS patients using conventional methods and next generation sequencing. All expert clinicians across Turkey are part of this work along with our bioinformatics partners and current and former students of NDAL, who are/were involved in this research.
The study cohort consists of 1200 unrelated Turkish ALS cases, 246 of whom are fALS (20%) and 954 are (80%) sALS patients. The male to female ratio is 1.5:1. Sixty percent of the cohort has an age of onset beyond 45 years. The initial symptoms were spinal in 64% and bulbar in 18%, 7% showed mixed site of onset.
The four major ALS genes (C9ORF72, SOD1, TDP-43, FUS) contribute to 35% of fALS and 6.1 of sALS in the Turkish cohort (as compared to 70% of fALS solved with four genes in European and N. American populations), pointing to a marked locus heterogeneity. The most common gene mutation in the ALS cohort under study is the hexanucleotide repeat expansion in C9Orf72 (17%), followed by SOD1 (13%), TDP-43 (3%) and FUS (2%) mutations. Whole exome sequencing detected pathogenic variants in another 10% of fALS and 4% of sALS.
Whole exome sequencing marks a turning point in disease gene identification, solving many previously unidentified cases. WES at NDAL, with a success rate approaching 50% in consanguineous families, unraveled variants in rare genes associated with diverse motor neuron phenotypes with upper or lower motor neuron predominance, revealing a great locus heterogeneity. This heterogeneity does not only expand our knowledge on the wealth of genes giving rise to motor neuron degeneration, but it also emphasizes pleiotropic effects and extensive phenotypic variation associated with specific ALS genes, possibly calling for the development of a more sophisticated taxonomy, eg gene-based classification of these diseases.
Currently, the Turkish population is one of the highly represented groups in Project MinE in terms of samples sequenced. Analyses of WGS data of the Turkish cohort consisting of 623 patients and 142 healthy controls revealed 47,971,649 novel variants, not represented in gnomAD. Out of all variants detected, 23,410,513 had a MAF smaller than 0.1% in the cohort. Although the Turkish population is expected to exhibit a unique genetic architecture, GWAS and gene-based burden analyses in the Turkish samples did not catch a population-specific local signal. This is not very unexpected, since in such analyses new disease-associated loci require very large sample sizes due to low frequencies of rare variants; this calls for more Turkish samples to be sequenced.