Browsing by Author "Başak, A. N."
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Item Open Access Assessment of the corticospinal fiber integrity in mirror movement disorder(Churchill Livingstone, 2018) Solmaz, B.; Özyurt, M. G.; Ata, D. B.; Akçimen, F.; Shabsog, M.; Türker, K. S.; Dalçik, H.; Algin, O.; Başak, A. N.; Özgür, M.; Çavdar, S.Mirror movements are unintended movements occurring on one side of the body that mirror the contralateral voluntary ones. It has been proposed that mirror movements occur due to abnormal decussation of the corticospinal pathways. Using detailed multidisciplinary approach, we aimed to enlighten the detailed mechanism underlying the mirror movements in a case subject who is diagnosed with mirror movements of the hands and we compared the findings with the unaffected control subjects. To evaluate the characteristics of mirror movements, we used several techniques including whole exome sequencing, computed tomography, diffusion tensor imaging and transcranial magnetic stimulation. Computed tomography showed the absence of a spinous process of C5, fusion of the body of C5-C6 vertebrae, hypoplastic dens and platybasia of the posterior cranial fossa. A syrinx cavity was present between levels C3-C4 of the spinal cord. Diffusion tensor imaging of the corticospinal fibers showed disorganization and minimal decussations at the lower medulla oblongata. Transcranial magnetic stimulation showed that motor commands were distributed to the motor neuron pools on the left and right sides of the spinal cord via fast-conducting corticospinal tract fibers. Moreover, a heterozygous missense variation in the deleted in colorectal carcinoma gene has been observed. Developmental absence of the axonal guidance molecules or their receptors may result in abnormalities in the leading of the corticospinal fibers. Clinical evaluations and basic neuroscience techniques, in this case, provide information for this rare disease and contribute to our understanding of the normal physiology of bimanual coordination.Item Open Access The genetic structure of the Turkish population reveals high levels of variation and admixture(National Academy of Sciences, 2020-12-18) Kars, Meltem Ece; Başak, A. N.; Onat, Onur Emre; Bilguvar, K.; Choi, J.; Itan, Y.; Çağlar, C.; Palvadeau, R.; Casanova, J.-L.; Cooper, D. N.; Stenson, P. D.; Yavuz, A.; Buluş, H.; Günel, M.; Friedman, J. M.; Özçelik, TayfunThe construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 30% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes.Item Open Access Human CRY1 variants associate with attention deficit/hyperactivity disorder(American Society for Clinical Investigation, 2020) Onat, O. Emre; Kars, M. Ece; Gül, Ş.; Bilguvar, K.; Wu, Y.; Özhan, Ayşe; Aydın, C.; Başak, A. N.; Trusso, M. A.; Goracci, A.; Fallerini, C.; Renieri, A.; Casanova, J-L.; Itan, Y.; Atbaşoğlu, C. E.; Saka, M. C.; Kavaklı, İ. H.; Özçelik, TayfunAttention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as “circiatric” disorders.Item Open Access Revisiting the complex architecture of ALS in Turkey: expanding genotypes, shared phenotypes, molecular networks, and a public variant database(John Wiley and Sons, 2020) Tunca, C.; Şeker, T.; Akçimen, F.; Coşkun, C.; Bayraktar, E.; Palvadeau, R.; Zor, S.; Koçoğlu, C.; Kartal, E.; Şen, N. E.; Hamzeiy, H.; Özoğuz-Erimiş, A.; Norman, Utku; Karakahya, Oğuzhan; Olgun, Gülden; Akgün, T.; Durmuş, H.; Şahin, E.; Çakar, A.; Başar-Gürsoy, E.; Babacan-Yıldız, G.; İşak, B.; Uluç, K.; Hanağası, H.; Bilgiç, B.; Turgut, N.; Aysal, F.; Ertaş, M.; Boz, C.; Kotan, D.; İdrisoğlu, H.; Soysal, A.; Uzun-Adatepe, N.; Akalın, M. A.; Koç, F.; Tan, E.; Oflazer, P.; Deymeer, F.; Taştan, Ö.; Çiçek, A. Ercüment; Kavak, E.; Parman, Y.; Başak, A. N.The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with ~70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well‐established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome‐wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease‐associated candidates, points to a significant enrichment for cell cycle‐ and division‐related genes. Within this network, literature text‐mining highlights DECR1, ATL1, HDAC2, GEMIN4, and HNRNPA3 as important genes. Finally, information on ALS‐related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser (www.gendal.org).