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.