Turkey

In the paediatric neurology clinic of Dokuz Eylül University’s School of Medicine, we examine approximately 6,500 patients annually. Neuromuscular patients constitute about 10-15% of this cohort. We examine around 10-15 new neuromuscular patients every month. We have a heterogeneous cohort of neuromuscular disorders due to consanguineous marriages in Turkey. Besides Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) for which we are able to provide a genetic diagnosis, our cohort mostly includes limb girdle muscular dystrophy, congenital muscular dystrophy, congenital myasthenic syndromes, metabolic muscle disorders and hereditary axonal polyneuropathies. We can give definite genetic diagnosis to 20-30% of these patients.

Tepecik GDC is now one of the most advanced diagnostic centres in Turkey and supports 8 Medical Genetics Specialist MDs and 21 lab staff. Since 2010, Tepecik Genetic Diagnosis Center (GDC) has been conducting diagnostic services in the fields of Cytogenetics and Molecular Genetics in patients consulted by clinics in Tepecik Hospital and other hospitals in the Aegean Region. Approximately 25,000 patients are admitted to Tepecik GDC annually, and approximately 15,000 tests are performed. The patient cohort includes a substantial number of suspected neuromuscular cases, with over 700 outpatients. Within this cohort, a genetic diagnosis is currently reached for over a quarter of patients. 

Izmir Biomedicine and Genome Center (IBG) is a recently-established biomedical centre of exceptional physical infrastructure over 20,000m2. The centre is equipped with state-of-the-art facilities including zebrafish and mouse facilities, high- resolution imaging and FACS cores, BSL3/ABSL3 facilities. Its genomics and bioinformatics facilities are equipped with NGS instruments and high-performance computing systems, as well as a biobanking facility.

At Tepecik GDC, for routine NGS diagnostic aims, an Illumina MiSeq and a Thermo Fisher Ion S5 NGS Systems are available. Apart from these, for Whole Exome/Whole Genome Sequencing and Non-invasive Prenatal Diagnosis, a BGISEQ-500 device (BGI) is also used. Tepecik GDC is the first and only lab in the country using Neuromuscular Disorders NGS panels for routine diagnosis.

For neuromuscular or neurometabolic diseases, TruSight Inherited Disease Gene Panel (Illumina) covering 552 genes is being used, with hundreds of samples processed to date.  Whole exome sequencing was also introduced for undiagnosed cases in 2019.

In our cytogenetics lab, SNP based Microarray system from Affymetrix is used. In 2017, we published our first results which represented the largest number of Affymetrix Optima Microarray results in Europe and the first in Turkey.

One of the major focus areas of IBG is Rare Diseases and we have strong collaborative ties with the Department of Paediatric Neurology in the Dokuz Eylul University Faculty of Medicine. The Neuro-Genomics Lab, also headed by Dr Yavuz Oktay, focuses on the underpinning genetic causes of rare diseases of the nervous system. His lab utilizes a wide array of methods and approaches (i.e. NGS, patient cell analysis, CRISPR etc.) to identify and model genomic variants that cause disease.

Professor Semra Hız and Professor Uluç Yiş at Dokuz Eylul University Pediatric Neurology have extensive experience in a wide spectrum of neurological and neuromuscular disorders. Together with collaborators in Malatya and Diyarbakir, Turkey, they have successfully established and performed deep-phenotyping of a 200-family cohort from consanguineous marriages. Genomic analyses of this cohort has identified about 20 new disease genes causing various neurologic and neuromuscular phenotypes. In collaboration with researchers at IBG and Tepecik GDC, they have been spearheading efforts in genomic analysis of such patients in Izmir and the Western part of Turkey.

• Yiş U, Diniz G, Hazan F, Daimagüler HS, Baysal BT, Baydan F, Akıncı G, Ünalp A, Aktan G, Bayram E, Hız S, Paketçi C, Okur D, Özer D, Danyeli AE, Polat M, Uyanık G, Çırak S. Childhood onset limb-girdle muscular dystrophies in the Aegean part of Turkey. Acta Myologica;XXXVII:p. 210-220.
• Yiş U, Becker K, Kurul SH, Uyanik G, Bayram E, Haliloğlu G, Polat Aİ, Ayanoğlu M, Okur D, Tosun AF, Serdaroğlu G, Yilmaz S, Topaloğlu H, Anlar B, Cirak S, Engel AG. Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights. J Child Neurol. 2017 Jul;32(8):759-765.
• Yiş U, Uyanik G, Rosendahl DM, Carman KB, Bayram E, Heise M, Cömertpay G, Kurul SH. Clinical, radiological, and genetic survey of patients with muscle-eye-brain disease caused by mutations in POMGNT1. Pediatr Neurol. 2014 May;50(5):491-7.
• Karakaya M, Mazaheri N, Polat I, Bharucha-Goebel D, Donkervoort S, Maroofian R, Shariati G, Hoelker I, Monaghan K, Winchester S, Zori R, Galehdari H, Bönnemann CG, Yis U, Wirth B. Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with variable clinical presentation. Brain. 2017 Oct 1;140(10):e65.
• Ozyilmaz B, Kirbiyik O, Koc A, Ozdemir TR, Kaya OO, Guvenc MS, Erdoğan KM, Kutbay YB. Experiences in microarray-based evaluation of developmental disabilities and congenital anomalies. Clin Genet. 2017 Oct;92(4):372-379.
• Karaoglu P, Quizon N, Pergande M, Wang H, Polat AI, Ersen A, Özer E, Willkomm L, Hiz Kurul S, Heredia R, Yis U, Selcen D, Çirak S Dropped head congenital muscular dystrophy caused by de novo mutations in LMNA. Brain Dev. 2017 Apr;39(4):361-364

Turkey has one of the youngest and largest populations in Europe, with high consanguineous marriage rates and the population is composed of many ethnic backgrounds. The proposed project will contribute a great deal to understanding the genetic basis of neuromuscular disorders in Turkey. Through supporting research to increase the number of patients with a precise genetic diagnosis, we will increase our experience of clinical phenotypes and ability to provide prenatal diagnosis to affected families. Becoming a part of the new international centre could also help tremendously with strengthening collaborations between the centres in the UK, Izmir and Ankara. Long lasting benefits of the ICGNMD will include advancing the clinical and research capacity of the centres involved, which will mature in time into local centres of excellence on neuromuscular disorders.

In the medical genetic outpatient clinic of Ankara City Hospital we examine neuromuscular patients referred from the child neurology clinic of Ankara City Hospital, other clinics in Ankara, and cities across Turkey. These patients constitute 5% of our total patient cohort and include suspected Duchenne muscular dystrophy and spinal muscular atrophy, Iimb girdle muscular dystrophy, congenital muscular dystrophy, congenital myasthenic syndromes, metabolic muscle disorders, Charcot Marie Tooth Disease, other hereditary polyneuropathies.

Patients with a pre-diagnosis of neuromuscular disease are evaluated at the medical genetic outpatient clinic for medical history, clinical features and pedigree analyses. This informs the choice of relevant, in-house genetic tests including chromosome analysis, chromosomal microarray, DMD MLPA, SMA MLPA, Charcot Marie Tooth MLPA, NGS panels (Duchene muscular dystrophy panel, muscular dystrophy panel, Charcot Marie Tooth neuropathy panel, autosomal recessive disease panel, clinical-exome panel and mitochondrial panels). Those patients who remain without a genetic diagnosis after this are evaluated by the genetic council for performing whole exome sequencing. A genetic diagnosis is currently deliverable in approximately 20-50% of neuromuscular disease patients.  

Ankara Yıldırım Beyazıt University supports almost 4,000 academic staff and 14,000 Turkish and international students. Its activities span 10 faculties, 2 vocational schools, 1 State Conservatory, 3 Institutes and 1 Core Research Center.

The Faculty of Medicine and Ankara City Hospital entered a shared-use agreement in 2019 to facilitate medical research.

The Ankara City Hospital Genetics Diseases Diagnostic Center consists of outpatient clinics, and laboratory divided into 3 subsections of prenatal and postnatal cytogenetics, molecular cytogenetics, and molecular facilities, and supports 10 medical geneticists, 3 medical genetics residency students, and 18 laboratory staff. Medical Genetics laboratories are supported via state-private enterprise co-operation, with laboratory staff supported by Siemens Healthineers). In its first 18 months after opening in Febraury 2019, over 25,000 patients were referred from across Turkey to be genetically tested and diagnosed with various genetic diseases including learning disorders, facial dysmorphism syndromes, neuromuscular or metabolic diseases, skeletal dysplasias, sex developmental disorders, endocrinological disorders, hematologic malignancies, hereditary cancer syndromes, and dermatological diseases.

• Dr. Semerci Gündüz is interested in elucidating the genetic etiology of the dysmorphic syndromes especially anophthalmia-microphthalmia and triphalangeal thumb-preaxial polydavtyly. She is experienced in prenatal and postnatal cytogenetics, molecular cytogenetics and DNA sequencing.
• Dr. Gulec Ceylan is interested in rare diseases and cancer genetics. She also has specialist expertise in DNA sequencing and molecular analysis techniques.
• Dr. A. C. Ceylan is interested in rare diseases. He has experience of chromosomal microarray analysis and next-generation DNA sequencing analysis.
• Dr. Kurt is interested in rare diseases. He has experience of molecular cytogenetics, real time PCR and DNA sequencing analysis.
• Dr. Cavdarli is interested in the clinical and molecular diagnosis and management of rare diseases including dysmorphic syndromes, neurogenetic and metabolic diseases.  She is experienced in targeted next-generation panel analyses as well as whole-exome sequencing. Dr. Cavdarli has also a great interest in clinical bioinformatics including big data analyses, variant interpretation, and clinical reporting.

• Semerci CN, Kalay E, Yıldırım C, Dinçer T, Ölmez A, Toraman B, Koçyiğit A, Bulgu Y, Okur V, Şatıroğlu-Tufan L, Akarsu NA. Novel Splice-Site and Missense Mutations in the ALDH1A3 Gene Underlying Autosomal Recessive Anophthalmia/Microphthalmia. Br J Ophthalmol;98:832–840 (2014).
• Dinçer T, Yorgancıoğlu-Budak G, Ölmez A, Er İ, Dodurga Y, Özdemir ÖM, Toraman B, Yıldırım A, Sabir N, Akarsu NA, Semerci CN, Kalay E. https://www.ncbi.nlm.nih.gov/pubmed/28832566 Eur J Hum Genet. 2017 Oct;25(10):1118-1125.
• Ceylan GG, Önalan E, Kuloğlu T, Aydoğ, Keleş İ, Tonyalı Ş, Ceylan C. Potential Role of Melastatin-Related Transient Receptor Potential Cation Channel Subfamily M Gene Expression in the Pathogenesis of Urinary Bladder Cancer. Oncology Letters, 2016;12:5235-5239.
• Ceylan GG, Ceylan C, Gülmemmedov B, Tonyalı Ş, Gözalan A, Keleş İ, Öztürk E. Polymorphisms of eNOS, catalase, and myeloperoxidase genes in prostate cancer in Turkish men: preliminary results. Genet Mol Res. 2016 Aug 19;15(3).
• Ceylan, A. C., Erdem, H. B., Şahin, İ., & Agarwal, M. (2020). SMN1 gene copy number analysis for spinal muscular atrophy (SMA) in a Turkish cohort by CODE-SEQ technology, an integrated solution for detection of SMN1 and SMN2 copy numbers and the “2+ 0” genotype. Neurological Sciences, 1-10. DOI:10.1007/s10072-020-04365-x.
• Ceylan, A. C., Arslan, E. A., Erdem, H. B., Kavus, H., Arslan, M., & Topaloğlu, H. (2020). Autosomal recessive spinocerebellar ataxia 18 caused by homozygous exon 14 duplication in GRID2 and review of the literature. Acta Neurologica Belgica, 1-6. DOI: 10.1007/s13760-020-01328-z.
• Cavdarli B, Percin EF, Karaoguz MY, Ergun MA. Diagnostic yield of molecular karyotyping of idiopathic intellectual disability patients ended with one causative anomaly; duplication 9q34 syndrome. Gazi Med J,2019; 30: 252-257 10.12996/gmj.2019.64.
• Yuksel, D., Oguz, K. K., Azapagası, E., Kesici, S., Cavdarli, B., Konuskan, B., & Topaloglu, H. (2018). Uncontrolled inflammation of the nervous system: Inherited CD59 deficiency. Neurology: Clinical Practice, 10-1212.