Queen Square Centre for Neuromuscular Diseases



Izmir Biomedicine and Genome Center and Institute (IBG) /
Dokuz Eylul University,
Faculty of Medicine, Department of Pediatrics Division of Child Neurology, Izmir

DEU Children's Hospital

Dokuz Eylul University Children's Hospital, Izmir

Tepecik Genetic Diagnosis Centre

Lead PI
Yavuz Oktay, PhD, Assistant Professor of Molecular Biology and Genetics

Yavuz Oktay

Ayşe Semra Hız, MD, Professor of Pediatrics and Pediatric Neurology
Uluç Yiş, MD, Professor of Pediatrics and Pediatric Neurology
Ayşe İpek Polat, MD, Specialist of Pediatrics and Pediatric Neurology
Figen Baydan, MD, Associate Professor of Pediatrics and Pediatric Neurology
Gülden Diniz, MD, PhD, Associate Professor of Pathology
Berk Özyılmaz, MD, Specialist of Medical Genetics

Clinical neuromuscular expertise, patients and geographical region:
In the child neurology clinic of Dokuz Eylül University, School of Medicine, we examine about 6,500 patients annually. Neuromuscular patients constitute about 10-15% of this cohort. We examine about 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 and spinal muscular atrophy in which we do not have challenges in 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 the patients.

Since 2010, Tepecik Genetic Diagnosis Center (GDC) has been conducting diagnostic services in the fields of Cytogenetics and Molecular Genetics in patients consulted by the clinics in Tepecik Hospital and clinics from the other hospitals in Aegean Region. Approximately 25,000 patients are admitted to Tepecik GDC annually, and approximately 15,000 tests are performed. With this performance Tepecik GDC has become one of the most advanced centers in Turkey. The center has 8 Medical Genetics Specialist MDs, and 21 lab. staff.

At Tepecik Neuromuscular Disorders Unit, until now, 252 patients suspected to have SMA; 98 patients suspected to have CMT1A diagnosis; 102 patients suspected to have Myotonic Dystrophy Type 1; 139 patients suspected to have DMD/BMD; 74 patients suspected to have LGMD; 51 patients suspected to have Congenital Myopathy and 30 patients suspected to have Congenital Muscular Dystrophy, were evaluated with molecular genetic methods. In these patients, diagnosis was achieved in 195 of 746 patients (26.1%).

Genetics and preclinical science expertise and facilities:
Izmir Biomedicine and Genome Center (IBG) is a recently established biomedical centre of exceptional physical infrastructure with more than 20,000 square meters of lab and office space. The centre is equipped with state-of-the-art facilities including zebrafish and mouse facilities, high- resolution imaging and FACS cores, BSL3/ABSL3 facilities, genomics and bioinformatics facilities equipped with NGS instruments and high-performance computing systems, as well as a biobanking facility.

Izmir Biomedicine and Genome Centre and Institute

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

For the neuromuscular or neurometabolic diseases, TruSight Inherited Disease Gene Panel (Illumina) covering 552 genes is being used. With this gene panel more than 500 samples have been analysed as of February 2019. Since the begining of 2019, whole exome sequencing has started to being used for undiagnosed cases.

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

Current research programmes:
One of the major focus areas of IBG is Rare Diseases and has strong collaborative ties with Dokuz Eylul University Faculty of Medicine Dept. of Pediatric Neurology. Neuro-Genomics Lab headed by Dr.Yavuz Oktay focuses on underpinning the 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.

Prof.Semra Hız and Prof.Uluç Yiş at DEU Pediatric Neurology has 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 the efforts in genomic analysis of such patients in Izmir and Western part of Turkey.

Top five publications from the past five years:
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.

How the new international centre will benefit research and clinical programmes:
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 answering the genetic basis of neuromuscular disorders in Turkey. Increasing the number of patients with a precise genetic diagnosis will increase our experience on clinical phenotypes and allow us to provide prenatal diagnosis to the affected families. Becoming a part of the new international centre could also help tremendously with strengthening the collaboration between the three centres in Izmir, as well as Ankara. Long lasting effects of the centre will be through advancing the clinical and research capacity of the centres involved, which will mature in time into a local centre of excellence on neuromuscular disorders.