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4. Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study

Author

Karacan, İlker, Balamir, Ayşe, Uğurlu, Serdal, Aydın, Aslı Kireçtepe, Everest, Elif, Zor, Seyit, Önen, Merve Özkılınç, Daşdemir, Selçuk, Özkaya, Ozan, Sözeri, Betül, Tufan, Abdurrahman, Yıldırım, Deniz Gezgin, Yüksel, Selçuk, Ayaz, Nuray Aktay, Ömeroğlu, Rukiye Eker, Öztürk, Kübra, Çakan, Mustafa, Söylemezoğlu, Oğuz, Şahin, Sezgin, Barut, Kenan, Adroviç, Amra, Seyahi, Emire, Özdoğan, Huri, Kasapçopur, Özgür, and Turanlı, Eda Tahir

Published
2019
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6. Correction to: Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study

Author

Karacan, İlker, Balamir, Ayşe, Uğurlu, Serdal, Aydın, Aslı Kireçtepe, Everest, Elif, Zor, Seyit, Önen, Merve Özkılınç, Daşdemir, Selçuk, Özkaya, Ozan, Sözeri, Betül, Tufan, Abdurrahman, Yıldırım, Deniz Gezgin, Yüksel, Selçuk, Ayaz, Nuray Aktay, Ömeroğlu, Rukiye Eker, Öztürk, Kübra, Çakan, Mustafa, Söylemezoğlu, Oğuz, Şahin, Sezgin, Barut, Kenan, Adroviç, Amra, Seyahi, Emire, Özdoğan, Huri, Kasapçopur, Özgür, and Turanlı, Eda Tahir

Published
2019
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7. Frequency and Severity of COVID‐19 in Patients with Various Rheumatic Diseases Treated Regularly with Colchicine or Hydroxychloroquine

Author

Oztas, Mert, primary, Bektas, Murat, additional, Karacan, Ilker, additional, Aliyeva, Numune, additional, Dag, Ayten, additional, Aghamuradov, Sarvan, additional, Cevirgen, Selim Berke, additional, Sari, Selma, additional, Bolayirli, Murat, additional, Can, Gunay, additional, Hatemi, Gulen, additional, Seyahi, Emire, additional, Ozdogan, Huri, additional, Gul, Ahmet, additional, and Ugurlu, Serdal, additional

Published
2022
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9. SCREENING SLC2A1 GENE FOR SEQUENCE AND COPY NUMBER VARIATIONS ASSOCIATED WITH GLUT-1 DEFICIENCY SYNDROME

Author

Ornek Erguzeloglu, Cemre, Kara, Bulent, Karacan, Ilker, Ozdemir, Ozkan, Kesim, Yesim, Bebek, Nerses, Ozbek, Ugur, Ugur Iseri, Sibel Aylin, Ornek Erguzeloglu, Cemre, Kara, Bulent, Karacan, Ilker, Ozdemir, Ozkan, Kesim, Yesim, Bebek, Nerses, Ozbek, Ugur, and Ugur Iseri, Sibel Aylin

Abstract

Objective: Glucose transporter-1 deficiency syndrome (GLUT1- DS) is defined as a metabolic encephalopathy that is associated with heterozygous and usually de novo pathogenic variations in the SLC2A1 (solute carrier family2 member1) gene. Materials and Methods: In this study, all coding exons and neighboring intronic regions of SLC2A1 were Sanger sequenced in 12 patients with clinically suspected GLUT1-DS. For de novo variations revealed after sequencing and segregation analysis, we also performed genome wide Single Nucleotide Polymor- phism (SNP) genotyping to confirm parental relatedness with the proband. In patients without any sequence variations, real-time quantitative real-time polymerase chain reaction (qPCR) was applied to determine the presence of any copy number variations (CNV). Results: Sanger sequencing followed by bioinformatics analysis, segregation in the family and SNP array genotyping revealed two novel and de novo pathogenic variations associated with the GLUT1-DS phenotype in 2 patients. qPCR results were compatible with one copy loss of SLC2A1 gene in another patient. All variations identified herein are likely to have caused null al-leles and resulted in GLUT1-DS through haplo insufficiency. Disscussion : In this study we used a series of molecular genetic approaches in order to identify all possible variations in SLC2A1 that may be associated with GLUT1-DS. This collective effort fa- cilitated diagnosis in 3 patients.

Published
2020

10. Genomic Diversity of the SARS-CoV-2 in Turkey and the Impact of Virus Genome Mutations on Clinical Outcomes

Author

Karacan, Ilker, primary, Akgun, Tugba Kizilboga, additional, Agaoglu, Nihat Bugra, additional, Zolfagharian, Payam, additional, Aydin, Mehtap, additional, Alkurt, Gizem, additional, Yildiz, Jale, additional, Kose, Betsi, additional, Can, Nisan Denizce, additional, Ozel, Ayse Serra, additional, Altunal, Nilsun, additional, Irvem, Arzu, additional, Demirkol, Yasemin Kendir, additional, Dogan, Ozlem Akgun, additional, Doganay, Levent, additional, and Doganay, Gizem Dinler, additional

Published
2020
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13. Bağlantı ve ekzom analizleri kullanarak hastalık geni keşfi

Author

Karacan, İlker, Tahir Turanlı, Eda, and Moleküler Biyoloji-Genetik ve Biyoteknoloji Ana Bilim Dalı

Subjects
Genetics, Genetik
Abstract

Nadir hastalıklar toplumda her 10.000 kişiden 5'inden daha azında görülen, genellikle yaşamı tehdit eden veya ağır kronik bulguları olan hastalıklar olarak tanımlanmaktadır. Dünyada 6.000'den fazla nadir hastalık bulunduğu ve toplumdaki sıklığının %6-8 arasında olduğu öngörülmektedir. Bu hastalıkların herbiri nadir olsa da, toplamda Türkiye'de 5 milyon kişinin nadir hastalıklardan etkilendiği düşünülmektedir. Bu hastalıkların yaklaşık %80'i genetik kökenli olup, erken yaşta ortaya çıkan ve ilerleyen hastalıklardır. Geri kalanı ise nadir kanserler, enfeksiyonlar, dejeneratif hastalıklar veya çevresel etkenlerden kaynaklanan hastalıklardır. Bu hastalıkların tekil olarak etkiledikleri hasta sayısı az olduğundan, geliştirilen tedavi yöntemleri kısıtlıdır. Nadir hastalıkların %95'inin henüz bir tedavisi yoktur. Çoğunluğu genetik olduğundan, büyük oranda çocukluk çağında ortaya çıkar ve hastaların %30'u beş yaşından önce hayatını kaybeder. Buna karşın, tanı koymadaki zorluklardan dolayı, ortalama bir hastanın doğru tanıyı alması sekiz yıl sürmekte, bu süre içerisinde 10 uzmanın klinik değerlendirmesinden geçmekte ve üç hatalı tanı almaktadır. Bu nedenlerden dolayı nadir bir hastalığın sebebini tespit ederek, ortaya çıkmadan önüne geçmek büyük önem taşımaktadır.Kalıtsal nadir hastalıklar genellikle yüksek etkili nadir genetik varyantlardan kaynaklanmaktadır. Bu genetik alleller genellikle yaşamı tehdit ettiğinden ve üreme çağından önce ortaya çıkarak sonraki nesillere aktarılamadığından dolayı negatif seçilim ya da elenme baskısı altındadır. Baskın genetik hastalıklara sebep olan alleler genellikle üreme üzerindeki etkilerinden dolayı sonraki nesillere aktarılamazken, bu hastalıklar de novo mutasyon oluşumlarıyla popülasyondaki sıklıklarını korurlar. Bunun yanı sıra çekinik genetik hastalıklara sebep olan alleller ise heterozigot durumda bireylerin sağlığını etkilemeden bulunabilirler. Akraba evliliğinin sık olduğu ülkelerde, çekinik hastalıklar diğer ülkelere göre daha yaygın görülmektedir. Türkiye İstatistik Kurumu raporlarına göre Türkiye'deki akraba evliliği oranı %23,2 olup, bunların büyük kısmı birinci derece kuzenler arasında olmaktadır. Bu durum ülkemizdeki akraba evliliği sebepli çekinik kalıtılan hastalıkların beklenenden daha çok insanı etkilemesine yol açmaktadır.Gelişen genomik teknolojilerin insan genetiği alanında kullanılmasıyla hastalık geni haritalanması artık daha etkili olarak gerçekleştirilebilmektedir. Yüksek çözünürlüklü genotiplendirme çalışmaları sayesinde bir kişi aynı anda milyonlarca tek nükleotid polimorfizmi (SNP) için genotiplenebilmekte ve genomundaki yapısal değişimler tespit edilebilmektedir. Genom-boyu elde edilen SNP genotip bilgisi kullanılarak bağlantı analizi ve homozigotluk haritalama yöntemleri sayesinde aile çalışmaları ile hastalıkla birlikte kalıtılan genom bölgeleri tespit edilebilmektedir. Ayrıca, DNA dizileme teknolojilerindeki gelişmeler sayesinde de genom dizileme metodları kullanılarak insan genomunun tümü veya yalnızca kodlayan bölgelerinin dizilenmesi mümkün olabilmektedir. Bu yöntemler özellikle kalıtım modeli öngörülebilen, birden fazla etkilenmiş bireyi bulunan geniş ailelerde daha yüksek başarı ile hastalık geninin haritalanmasını sağlayabilmektedir. Bu amaç ile, aile çalışmalarında ilk olarak genom-boyu analizler ile, aile içerisinde hastalıkla birlikte kalıtılan kromozom bölgelerinin tespit edilmesi gerekmektedir. Elde edilen hastalık-ilişkili olabilecek aday bölgelerin DNA dizisinin incelenmesi ile de hastalığa yol açan genetik değişimler tespit edilebilmektedir.İnsan genomunda 20.000'den fazla sayıda gen olmasına rağmen, bunların birçoğunun fonksiyonu ile ilgili henüz yeterli bilgi mevcut değildir. Online Mendelian Inheritance in Man (OMIM) veritabanında, 1 Nisan 2019 tarihi itibarı ile, 4,000'den fazla gen için herhangi bir açıklama dahi mevcut değilken, Mendelyen kalıtım olduğu düşünülen 1,756 fenotipin ilişkilendirildiği bir gen veya lokus dahi bulunmamaktadır. Hastalık geni haritalama yöntemleri ile tespit edilecek gen-fenotip ilişkisi yardımı ile işlevi bilinmeyen birçok genin ilişkili olduğu biyokimyasal mekanizmalarının ortaya çıkarılması mümkün olabilecektir. Aynı zamanda, hastalığa sebep olan genlerin tespit edilmesiyle ailelerin sonraki nesillerde hasta çocuklarının olmasının önüne geçilebilmektedir. Buna ek olarak, hastalıklarla ilişkisi zaten bilinen genlerdeki bozuklukların, literatürdeki bilinenden farklı bulgulara sebep olması da, hastalığın tanısının konmasını kolaylaştırıcı yeni bilgiler üretmesine sebep olabilmektedir. Zaten nadir görülen bu hastalıkların yeni ek klinik bulgularının tespit edilmesiyle, bu hastalıklardaki tanı için geçen ortalama süreyi azaltabilecek veriler de elde edilebilir.Bu çalışmada, nadir tek gen hastalığı olan ailelerde hastalıktan sorumlu genetik varyantların bulunması amaçlanmıştır. Bu amaçla dört farklı hastalık için on ailede genom-boyu SNP genotiplendirme, bağlantı analizi ve/veya homozgiotluk haritalama tekniklerinin yanısıra aday gen ve/veya ekzom dizileme yöntemleri kullanılmıştır. Bu yöntemler her çalışılan aileye, hastalığa ve elde edilen veriye göre farklı kombinasyonlarda uygulanmıştır.Tezin ilk kısmında, klinik olarak ailesel Akdeniz ateşi (AAA) tanısı almış fakat hastalıktan sorumlu olduğu bilinen MEFV geninde hastalık yapıcı varyant bulunmayan iki aile incelenmiştir. Bu hastalardaki AAA-benzeri klinik profilin daha önce tanımlanmamış fenotipler olabileceği veya hastalık ilişkisi bilinmeyen genlerdeki bozuklukların genetik heterojenite sonucunda AAA bulgularına yol açabileceği hipotezi kurulmuş ve genetik analizler gerçekleştirilmiştir. İlk ailede hastalığın baskın geçişli kalıtıldığı öngörüldüğünden iki hastada (baba ve kız) ekzom dizileme yapılmıştır. Ham verinin biyoinformatik analizi ile ekzonik varyantlar incelenmiş, her iki hastada da ortak paylaşılanlar incelenmiştir. Sonuç olarak, tümör nekroz faktör reseptörüyle ilişkili periyodik sendrom (TRAPS) hastalığına yol açtığı bilinen TNFRSF1A geninde daha önce bildirilmemiş c.215G>T (p.Cys72Phe) varyantı heterozigot olarak tespit edilmiştir. İkinci ailede ise hastalığın çekinik geçişli olduğu öngörülmüş, genom-boyu SNP genotiplendirme verisi kullanılarak çekinik kalıtım modelinde çok noktalı parametrik bağlantı analizi gerçekleştirilerek hastalıkla ilişkili kromozom bölgeleri aranmıştır. Tespit edilen aday bölgeler arasında en büyüğünde (12 Mb) hastalıktan sorumlu olabilecek gen aranmış, bölgenin mevalonat kinaz eksikliği hastalığına sebep olduğu bilinen MVK genini barındırdığı görülmüştür. Gerçekleştirilen DNA dizi analizi sonucunda bu gende daha önce bildirilmemiş c.481T>C (p.Cys161Arg) değişimine sebep olan varyantın kalıtım modeli ile de uyumlu olarak, sadece hasta bireylerde homozigot durumda kalıtıldığı gösterilmiştir. Bu varyantın her iki ailenin hasta bireylerinde ayrıntılı klinik incelemeleriyle, AAA tanısını genetik bulguların desteklemediği durumlarda, klinik heterojenite de göz önünde bulundurularak, diğer otoinflamatuar hastalıklardan sorumlu genlerin de incelenmesi gerektiği sonucuna varılmıştır.Tezin ikinci kısmında, çocuk ve gençlerdeki en sık rastlanan romatolojik hastalık olan ve sebebi bilinmeyen kronik artrit ile karakterize juvenil idiyopatik artrit (JIA) hastalığı bulunan aileler incelenmiştir. JIA hastalığı kompleks kalıtımlı olarak bilinmekte olup, aile ve ikiz çalışmaları hastalığın oluşunda genetik faktörlerin de rol oynayabileceğini işaret etmektedir. Tez kapsamında akraba evliliği sonucunda ikişer hasta kardeş bulunan iki ailede genom-boyu SNP genotiplendirme verisi kullanılarak, çekinik kalıtım modelinde çok noktalı parametrik bağlantı analizi ile hastalıkla birlikte kalıtılan kromozom bölgeleri aranmıştır. İki ailede birden yapılan bağlantı analizi sonucunda en yüksek LOD skor 4.81 olarak 6.8 Mb'lık 13q13.3-13.14.13 bölgesinde hesaplanmıştır. Tespit edilen hastalık-ilişkili kromozom bölgesinde yer alan 38 protein kodlayan gen incelenmiş, daha önce nadir ailesel vakalarda hastalık-ilişkili olarak bildirilen ve çalışma sırasında da başka gruplar tarafından Mendelyen kalıtım gösteren JIA ailelerinde hastalık-ilişkili patojenik varyantlar tanımlanmış olan LACC1 geni en güçlü aday olarak belirlenmiştir. Bu ailelerde LACC1 geninin kodlayan bölgelerinin Sanger yöntemi ile dizilenmesi sonucunda sırasıyla başlangıç kodonunu bozan c.3G>A (p.0) ve erken bitiş kodonu oluşturan c.1240C>T (p.Arg414Ter; rs184370809) değişimleri kalıtım modeli ile uyumlu olarak sadece hasta bireylerde homozigot durumda tespit edilmiştir. Devamında çalışmaya dahil edilen ikişer hasta kardeş bulunan diğer beş ailede de LACC1 geninin kodlayan bölgeleri dizilenerek taranmıştır. Üçüncü ailede yine kalıtım modeli ile uyumlu olarak çerçeve kayması olmadan amino asit silinmesi yapan c.998_990del (p.Ile330del; rs776489319) varyantı tespit edilmiştir. Son ailede ise hasta bireylerde ortak genotipte, işlevsel etkisi bildirilen yaygın bir polimorfizm olan c.760A>G (p.Ile254Val; rs3764147) varyantı homozigot olarak, daha önce bildirilmemiş c.1109G>A (p.Cys370Tyr) varyantı ise heterozigot durumda tespit edilmiştir. Fakat bu ailede bir sağlıklı birey daha hastalarla aynı genotipte bulunduğundan, daha önce bildirilmemiş p.Cys370Tyr varyantının hastalık oluşumundaki rolü net olarak belirlenememiştir. Önceki yayınlanan çalışmalarla birlikte bu çalışmada da LACC1 geni bozukluklarının nadir görülen ailesel JIA vakalarında hastalıktan sorumlu olduğu belirlenmiş, erken başlangıçlı JIA vakalarında LACC1 gen analizinin göz önünde bulundurulması önerilmiştir. Diğer üç ailede ise LACC1 geninin kodlayan bölgelerinde herhangi bir nadir varyant tespit edilmemiştir.Tezin üçüncü kısmında ise, ilk klinik incelemelerde mikrosefali, zihinsel yetmezlik ve dismorfik bulguların yanında kanama eğilimi ile yetersiz yara iyileşmesi bulguları olan bir aile çalışılmıştır. Anne-baba akraba olup, hastalık bulgularını taşıyan iki hasta çocukları vardır. Hasta bireylerin çalışmaya dahil edilmeden önce tıbbi genetik birimlerinde yapılan kromozom analizinde ve hematolojik bulgularla ilişkili olabilecek aday genlerde hastalık yapıcı bir değişim tespit edilememiştir. Bu sebeplerle çekinik kalıtılan yeni bir hematolojik hastalık olabileceği hipotezi ile çalışmaya dahil edilmiştir. Aile bireylerinde genom-boyu SNP genotip verisi kullanılarak gerçekleştirilen çok noktalı parametrik bağlantı analizi sonucunda 12q24.21-24.32 kromozomal bölgesinde en yüksek LOD skor 2.59 olarak elde edilmiştir. Bu aday bölgedeki 112 protein kodlayan genin incelenebilmesi için ekzom dizileme gerçekleştirilmiştir. Ham verinin biyoinformatik analizi ile saptanan ekzonik varyantlar incelenerek önceliklendirilmiştir. Otozomal çekinik kutis laksa tip IIA (ARCL2A) hastalığına sebep olduğu bilinen ATP6V0A2 geninde daha önce bildirilmemiş, çerçeve kaymasına sebep olan c.2085_2088del (p.Ser695Argfs*) varyantı protein yapısını da bozması sebebiyle en güçlü aday olarak belirlenmiştir. Ailedeki hasta bireyler bu hastalık yönünden tekrar klinik olarak incelenmiş, onlarda ARCL2A bulgularından buruşuk ve gevşek deri gözlenmiştir. Tüm aile bireyleri aday varyant için taranmış, varyant kalıtım modeline uygun olarak yalnızca hasta bireylerde homozigot olarak tespit edilmiştir. Böylece, hastalığın ARCL2A ile uyumlu olduğu görülse de, mikrosefali dışında yapısal beyin bozukluğu, şaşılık, miyop, büyüme ve gelişme geriliği görülmediği, ama kanama eğilimi ve yetersiz yara iyileşmesi bulgularının varlığı tespit edilmiştir. Ailedeki hasta ve sağlıklı bireylerden alınan kan ve cilt dokusu örnekleri ışık ve elektron mikroskopisi çalışmalarıyla da incelenmiştir. Bu incelemeler, literatür bilgisi ile de uyumlu olarak, yalnızca hastalarda deri dokusunda elastik fiber eksikliğini doğrulamıştır. Ayrıca yalnızca hasta bireylerde büyük hacimli trombositler görülmüştür. Hastalardaki ek hematolojik bulguları açıklayacak başka bir genetik bozukluk tespit edilememiş olup, bu ek bulguların genel hücresel glikolizasyondaki bozulmanın etkisiyle von Willebrand faktör multimerizasyonunda veya trombosit yüzey glikoproteinlerinin işlevini etkileyerek yol açtığı düşünülmüştür.Sonuç olarak, tez çalışması kapsamında dört farklı nadir hastalıktan etkilenmiş ailelerde genom-boyu bağlantı, homozigotluk ve ekzom dizileme analizleri gerçekleştirilmiştir. Ailelerin hastalarında ayrıntılı klinik ve laboratuvar incelemelerinin yanısıra gerektiği durumlarda histolojik analizler de yapılmış, çalışmalar sonucunda bu hastalıklardan sorumlu daha önce bildirilmemiş genetik bozukluklar tespit edilmiş, bilinen hastalıklarda yol açtıkları yeni klinik bulgular belirlenerek rapor edilmiştir. Rare diseases are described as diseases with a prevalence of less than 5 in 10,000 individuals, life-threatening, or with severe symptoms. It has been predicted that there are more than 6,000 rare diseases with a prevalence of 6-8% worldwide. Although these diseases are individually rare, in total 5 million people in Turkey are estimated to be affected by a rare disease. Eighty percent of these diseases are inherited, with early onset, and progressive. The remaining include rare cancers, infections and degenerative diseases with environmental causes. Treatment options for rare diseases are highly limited due to the small number of individuals affected by each rare disease; there is no available treatment for 95% of rare diseases. Since most of the rare diseases have genetic causes, the great majority of affected individuals develop the disease in childhood and 30% of them die before the age of five years. Furthermore, definite diagnosis usually takes eight years, ten clinical examinations by specialized clinicians, and three misdiagnosis due to difficulties in differential diagnosis. For these reasons, unraveling the underlying reasons for rare diseases and developing protective strategies have high importance. Heritable rare diseases are usually caused by high-risk, rare genetic variants which are under negative selection and impact before puberty and thus are not inherited through generations. Alleles responsible for dominantly inherited genetic diseases generally are not transmitted through generations because the affected individuals do not reproduce due to poor health; however, their incidences are stable due to de novo mutations. On the other hand, alleles responsible for recessively inherited genetic diseases generally have stabilized frequencies in the population, as heterozygous state does not effect individuals' health. Recessively inherited genetic diseases are more common in countries where consanguineous marriage rates are high. According to the Turkish Statistical Institute reports, average consanguineous marriage rate is 23.2% in Turkey and most of these marriages are between first cousins. This makes recessively inherited genetic diseases caused by consanguineous marriage affect more people than expected in our country. Use of recently developed genomic technologies have resulted in more effective gene mapping strategies in human diseases. Family members can be simultaneously genotyped with millions of single nucleotide polymorphisms (SNP), and structural changes can be detected by high-resolution genotyping analyses. Using the genome-wide SNP genotype data, genomic regions inherited together with diseases can be detected in family studies by linkage analysis and homozygosity mapping methods. Moreover, sequencing the whole human genome or only the coding regions is now possible due to recent developments in genetic technologies. These techniques are particularly successful in gene mapping in large families with multiply affected individuals and a well-defined inheritance model. Therefore, chromosomal regions inherited with the disease can be initially identified in family studies, as we all carry numerous deleterious mutations, even in homozygous state. Detection of the specific genetic variants causing the diseases can then be possible by DNA sequence analyses in the detected candidate regions.Although there are more than 20,000 genes in the human genome, there is not sufficient functional information about most of the genes. As of 1 April 2019, there is no description for over 4,000 genes and there is no associated gene or locus for 1,756 phenotypes with suspected Mendelian basis in Online Mendelian Inheritance in Man (OMIM) database. It will be possible to identify biochemical mechanisms for disease genes with unknown function with the help of gene-phenotype relationships. Additionally, disease transmission through generations can be prevented by the identifying the disease-causing genes responsible for the diseases. Moreover, identifying genes with known disease associations in different clinical outcomes can provide new insights in differential diagnosis. Detection of novel clinical features of these rare diseases may also shorten the period of an average of eight years for the definitive diagnosis. In this study, the aim was to identify disease-causing genetic variants in families with rare single-gene diseases. Genome-wide SNP genotyping, linkage analysis and/or homozygosity mapping as well as candidate gene and/or exome sequencing techniques were applied to ten families afflicted with four different diseases. The techniques were applied in different combinations for each family depending on disease and the available genetic data. In the first part of the thesis, two families afflicted with familial Mediterranean fever (FMF) diagnosis without any FMF-causing MEFV variants were investigated. The hypothesis was that FMF-like clinical manifestations in these patients may be undefined phenotypes or defects in genes without known disease association may result in FMF manifestations resulting in genetic heterogeneity, and genetic analyses were carried out accordingly. In the first family, exome sequencing was performed in two patients (father and daughter) since the disease inheritance pattern was assessed as dominant. Exonic variants were prioritized through bioinformatics analysis of the raw data and shared variants between the two patients were further analyzed. Novel c.215G>T (p.Cys72Phe) variant in TNFRSF1A gene, known to cause tumor necrosis factor receptor-associated periodic syndrome (TRAPS), was detected in the both patients in heterozygous state. In the second family, inheritance pattern was assessed as recessive and disease-associated chromosomal regions were searched through multipoint parametric linkage analysis using genome-wide SNP genotyping data. Among the detected regions, candidate disease-causing genes were searched in the largest region (12 Mb) in which mevalonate kinase deficiency-causing MVK gene resided. As a result of the DNA sequence analysis, novel c.481T>C (p.Cys161Arg) variant in MVK was detected in homozygous state in accordance with the inheritance pattern. Detailed clinical examination of the affected individuals in both families was carried out, and it was concluded that genes responsible for other autoinflammatory diseases should be considered whenever genetic findings do not support FMF diagnosis, considering the clinical heterogeneity.In the second part of the thesis, families with juvenile idiopathic arthritis (JIA), the most common rheumatological disease among children and juveniles, which is characterised by chronic arthritis of unknown basis, were investigated. Although JIA is known to have complex inheritance, family and twin studies indicate involvement of genetic factors in disease development. In two families with two affected siblings each and parental consanguinity, chromosomal regions inherited with the disease were searched through multipoint parametric linkage analysis under recessive inheritance model using genome-wide SNP genotype data. As a result of linkage analysis, highest LOD score of 4.81 was obtained in a 6.8 Mb region at 13q13.3-13.14.13. Thirty-eight protein-coding genes were evaluated, and LACC1 gene was assessed as the strongest candidate since the gene has been associated with JIA in rare familial cases. Coding regions of LACC1 were analysed by Sanger sequencing in all patients. Initiation codon-disrupting c.3G>A (p.0) and premature termination codon-causing c.1240C>T (p.Arg414Ter; rs184370809) variants were detected in homozygous state. Five more families with two affected siblings each were later included in the study, and coding regions of LACC1 gene were sequenced. Homozygous c.998_990del (p.Ile330del; rs776489319), causing non-frameshift single amino acid deletion, variant was detected in one of the families. In another family, common c.760A>G (p.Ile254Val; rs3764147) polymorphism (homozygous) with a known functional effect and novel c.1109G>A (p.Cys370Tyr) variant (heterozygous) were detected in patients. However, the same genotype was detected also in a healthy family member, and thus, the role of this novel variant in disease development is yet to be determined. In accordance with the previously published reports, LACC1 gene defects were found to be responsible for rare, familial JIA cases. We suggest that LACC1 gene should be considered for early-onset JIA cases. In the remaining three families, any coding rare variant was not detected in LACC1.In the third part of the thesis, a family afflicted with microcephaly, mental retardation, dysmorphic features as well as bleeding tendency and defective wound healing was studied. This family with parental consanguinity had two affected children. Before the enrolment of the family in the study, no disease-causing genetic defect had been detected in the chromosomal and candidate gene analyses. The hypothesis was that the hematological disease could be a novel recessive syndrome. As a result of the multipoint parametric linkage analysis performed using the genome-wide SNP genotype data, a highest LOD score of 2.59 was obtained in the chromosomal region 12q24.21-24.32. Exome sequencing was performed in the index patient to analyze the 112 protein-coding genes residing in this candidate region. Exonic variants were prioritised with bioinformatic analysis of the raw data. Novel frameshift c.2085_2088del (p.Ser695Argfs*) variant in ATP6V0A2 gene, which is known to be responsible for autosomal recessive cutis laxa type 2 (ARCL2A) disease, was assessed as the strongest candidate due to its protein structure altering-effect. Affected family members were clinically re-evaluated, and wrinkled skin, the major clinical finding of ARCL2A, was detected. All family members were tested for the candidate variant, and only patients were found homozygous, compatible with the inheritance model. Although the disease seems similar to ARCL2A, there was no strabismus, myopia, developmental delay, or structural brain defects except for microcephaly, and there was bleeding tendency with defective wound healing. In blood and skin tissues of family members examined by light and electron microscopy showed a decrease in mature elastic fiber structures in skin in patients concordant with the literature. Furthermore, large thrombocytes were detected in patients. No other genetic defect explaining the additional hematological findings was detected. Those additional hematological findings were hypothesised to be caused by defective global glycolization which could disrupt the von Willebrand factor multimerization or the function of the thrombocyte surface glycoproteins.In conclusion, in this thesis work genome-wide linkage, homozygosity and exome sequencing analyses were performed in families afflicted with four rare diseases. Detailed clinical and laboratory examinations as well as histological analyses were performed for the patients whenever required, and consequently novel genetic defects responsible for the diseases were identified and the novel clinical findings in diseases were determined and published. 88

Published
2019

16. Genetic Analysis of Inherited Autoinflammatory Disorders

Author

KARACAN, İLKER, Öztürk, Kübra, AKTAY AYAZ, NURAY, YÜKSEL, SELÇUK, UĞURLU, SERDAL, Özdoğan, Huri, GEZGİN YILDIRIM, DENİZ, KASAPÇOPUR, ÖZGÜR, Barut, Kenan, TUFAN, ABDURRAHMAN, Adrovic, Amra, ŞAHİN, SEZGİN, Özkılınç, Merve, Sevinç, Neslihan, TAHİR TURANLI, EDA, Kireçtepe Aydın, Aslı, Balamir, Ayşe, SEYAHİ, EMİRE, and ÖZKAYA, OZAN

Published
2017

17. The origin of SARS-CoV-2 in Istanbul: Sequencing findings from the epicenter of the pandemic in Turkey.

Author

Karacan, Ilker, Akgun, Tugba Kizilboga, Agaoglu, N. Bugra, Irvem, Arzu, Alkurt, Gizem, Yildiz, Jale, Kose, Betsi, Ozel, A. Serra, Altunal, L. Nilsun, Can, Nisan Denizce, Demirkol, Yasemin Kendir, Aydin, Mehtap, Dogan, Ozlem Akgun, Doganay, Levent, and Doganay, Gizem Dinler

Subjects
SARS disease, COVID-19 pandemic, NASOPHARYNX diseases, POLYMERASE chain reaction
Abstract

OBJECTIVE: Turkey is one of the latest countries that COVID-19 disease was reported, with the first case on March 11, 2020, and since then, Istanbul became the epicenter of the pandemic in Turkey. Here, we reveal sequences of the virus isolated from three different patients with various clinical presentations. METHODS: Nasopharyngeal swab specimens of the patients were tested positive for the COVID-19 by qRT-PCR. Viral RNA extraction was performed from the same swab samples. Amplicon based libraries were prepared and sequenced using the Illumina NextSeq platform. Raw sequencing data were processed for variant calling and generating near-complete genome sequences. All three genomes were evaluated and compared with other worldwide isolates. RESULTS: The patients showed various clinics (an asymptomatic patient, patient with mild disease, and with severe pulmonary infiltration). Amplicon-based next-generation sequencing approach successfully applied to generate near-complete genomes with an average depth of 2616. All three viral genomes carried the D614G variant (G clade according to GISAID classification) with implications for the origin of a spread first through China to Europe then to Istanbul. CONCLUSION: Here, we report the viral genomes circulating in Istanbul for the first time. Further sequencing of the virus isolates may enable us to understand variations in disease presentation and association with viral factors if there is any. In addition, the sequencing of more viral genomes will delineate the spread of disease and will guide and ease the necessary measures taken to stem the spread of the novel coronavirus. [ABSTRACT FROM AUTHOR]

Published
2020
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21. İdiyopatik jeneralize epilepsili ailelerde lokus ve gen analizi

Author

Karacan, İlker, Özbek, Uğur, and Genetik Anabilim Dalı

Subjects
Epilepsy, Genetics, Genetik
Abstract

Epilepsi dünyada görülen en yaygın nörolojik bozukluklardan biri olup, tüm epilepsi vakalarının 1/3'ü idiyopatik jeneralize epilepsi (İJE) olarak sınıflandırılmıştır. İJE etiyolojisindeki genetik faktörlerin etkisi bilinmektedir. İJE ile ilgili az sayıda kromozom veya gen bölgesinin hastalıkla ilişkili olduğu gösterilebilmiştir. Kalıtım paterninin kompleks olmasından ve birden fazla genin ve çevresel etmenlerin de epileptik nöbetler üzerinde etki gösterebilmesinden ötürü epilepsi genlerini belirleyebilmek oldukça zordur. Bu zorlukların yanında birçok etkilenmiş birey barındıran İJE aileleri epilepsi genlerini keşfetmekte büyük öneme sahiptir.Genetik bağlantı analizi hastalıkla ilişkili kromozom bölgelerinin tanımlanmasında kullanılan bir yöntemdir. Belirteç ve hastalık durumunun bireylerdeki dağılımının izlenmesiyle hastalığa sebep olan kromozom bölgelerini tespit etmek mümkündür. Bağlantı varlığı LOD skor olarak derecelendirilir.Bu projede otozomal çekinik kalıtım gösteren iki İJE ailesi EPICURE projesi kapsamında daha önce oluşturulmuş genotip verileri ve Illumina CytoSNP-12 mikroçipi ile tüm genom genotiplendirmesi yapılarak analiz edilmiştir. Ailelerden ilkinde en yüksek LOD skor 22q11.1-q11.21 bölgesinde 2,50 olarak hesaplanmıştır. İkinci ailede ise heterojen klinik bulgular dolayısı ile farklı parametrelerle çalışılmış fakat bağlantı analizi açısından yeterli anlamlılıkta bir sonuç bulunamamıştır. Ayrıca CytoSNP-12 ile genotiplenen bireylerdeki kopya sayısı değişimleri de incelenmiş, ailede hatalıkla birlikte kalıtılan kopya sayısı değişimi tespit edilmemiştir.Çalışma kapsamında erken başlangıçlı absans epilepsisi olan 17 birey ile GLUT1 yetmezliği sendromundan şüphelenilen 3 bireyin SLC2A1 geni mutasyon taraması gerçekleştirilmiştir. Yaygın polimorfizmler dışında NM_006516.2:c.516+38C>T ile NM_006516.2:c.680-1G>T değişimleri heterozigot olarak tespit edilmiştir. c.680-1G>T değişimi hastanın aile bireylerinde ve 94 sağlıklı kontrol örneğinde tespit edilememiştir. Değişimin alternatif kırpılma mekanizmasını etkilediği öngörülmüş, hasta ve ebeveynlerinin SLC2A1 geni rölatif anlatım seviyeleri -referans olarak ABL geni kullanılarak- GZ-PZR ile belirlenmiştir. Hastanın ebeveynlerine oranla %49 daha düşük seviyede SLC2A1 anlatımına sahip olduğu belirlenmiştir (p=0,0002). Tespit edilen mutasyonun de novo olduğu ve dominant etki ile hastalığa sebep olduğu düşünülmektedir. Epilepsy is one of the most common neurological disorders and approximately 1/3 of all epilepsy cases are classified as IGE. Only a few genes or chromosomal regions that is associated with IGE can be shown yet. It is hard to identify epilepsy genes because inheritance pattern is complex, there are possibly more than one major gene causing seizures and, environmental factors play a role on seizures. Beside its difficulties, IGE families with many affected individuals have substantial importance for exploring major epilepsy genes.Genetic linkage analysis is used to identify chromosomal regions of the genome that contain genes associated with disease. It is possible to detect localization of disease locus by observing segregation of marker and disease status in families. Evidence for linkage is expressed as a logarithm of the odds (LOD) score.In this project, two IGE families with autosomal recessive inheritance were analyzed using EPICURE genotyping data and Illumina CytoSNP-12 genotyping data. In first family, highest LOD score was estimated as 2.50 in region 22q11.1-q11.21. In another family, different parameters were used in linkage analysis due to clinical heterogeneity. However, any significant result for linkage analysis was not detected. Furthermore, copy number variations in all individuals genotyped with CytoSNP-12 were estimated but any variation that segregates with trait was not detected.In addition, 17 patients with early onset absence epilepsy and 3 patient suspected from GLUT1 deficiency syndrome were screened for mutations in SLC2A1. As a result, excluding common polymorphisms, heterozygous novel variations NM_006516.2:c.516+38C>T and NM_006516.2:c.680-1G>T were detected. c.680-1G>T was not detected neither her family members nor 94 healthy control samples. It is suggested that mutation alters the alternative splicing mechanism. SLC2A1 relative expression levels (ABL gene used as reference) were determined with RT-PCR method. As a result, patient has 49% decreased SLC2A1 transcript with respect to her parents (p=0.0002). Detected novel mutation in E11-169 occurred de novo and it is suspected as a dominant cause of disease. 81

Published
2012

23. Whole Genome Sequencing Analysis of Neisseria gonorrhoeae Isolates From Turkey: An Observational Study.

Author

YILMAZ, Gizem, KHAN, Asif M., KARACAN, İlker, and DOYMAZ, Mehmet Ziya

Subjects
NEISSERIA, WHOLE genome sequencing, NEISSERIA gonorrhoeae, SEQUENCE analysis, MEDICAL microbiology, SEXUALLY transmitted diseases
Abstract

Introduction: Neisseria gonorrhoea, the agent of sexually transmitted infections, remains a major public health concern. Whole genome sequencing (WGS) of the agent can provide insights on antimicrobial resistance, pathogenicity, and epidemiology of the bacteria, among others. The aim of this study is to sequence and characterize the whole genome of nine Neisseria gonorrhoeae strains and to understand their epidemiological origins, and the resistance determinant genes. Method: N. gonorrhoeae strains were obtained from different clinical microbiology laboratories. The isolates were cultured on Thayer-Martin medium and antimicrobial susceptibility test was done using disk diffusion method. DNA was extracted from bacterial suspensions using the DNA Kit and WGS sequencing was done. Genes involved in antimicrobial resistance were detected using various bioinformatics tools. Phylogenetic analysis based on 50S ribosomal protein L6 was carried out to determine the evolutionary origin of the isolates. Basic Local Alignment Search Tool search with the protein identified close homologs, which were aligned for maximum likelihood tree generation (bootstrap of 100). Results: Six of the N. gonorrhoeae isolates were susceptible to ceftriaxone and three of them were resistant or intermediate to penicillin. All N. gonorrhoeae isolates possessed norm, mtrC, mtrR, mtrF, mtrA, farB, DfrA42, macA, and macB genes as genetic resistance determinants. Only one isolate contained tetM gene, a tetracyclineresistant determinant. Phylogenetic analysis revealed that our strains formed a statistically significant clade with isolates from Korea, Canada, USA and Russia. Conclusion: The nine N. gonorrhoeae strains circulating in Turkey do not appear to pose a significant threat to public health since they do not have any novel antimicrobial resistance features. Phylogenetic analysis revealed that our clinical strains share common origin with isolates from diverse regions of the world. [ABSTRACT FROM AUTHOR]

Published
2022

24. Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

Author

Alm E., Broberg E.K., Connor T., Hodcroft E.B., Komissarov A.B., Maurer-Stroh S., Melidou A., Neher R.A., O'Toole A., Pereyaslov D., Beerenwinkel N., Posada-Cespedes S., Jablonski K.P., Ferreira P.F., Topolsky I., Avsic-Zupanc T., Korva M., Poljak M., Zakotnik S., Zorec T.M., Bragstad K., Hungnes O., Stene-Johansen K., Reusken C., Meijer A., Vennema H., Ruiz-Roldan L., Bracho M.A., Garcia-Gonzalez N., Chiner-Oms A., Cancino-Munoz I., Comas I., Goig G.A., Torres-Puente M., Lopez M.G., Martinez-Priego L., D'Auria G., Ruiz-Hueso P., Ferrus-Abad L., de Marco G., Galan-Vendrell I., Carbo-Ramirez S., Ruiz-Rodriguez P., Coscolla M., Polackova K., Kramna L., Cinek O., Richter J., Krashias G., Tryfonos C., Bashiardes S., Koptides D., Christodoulou C., Bartolini B., Gruber C.E., Di Caro A., Castilletti C., Stefani F., Rimoldi S.G., Romeri F., Salerno F., Polesello S., Nagy A., Jirincova H., Vecerova J., Novakova L., Cordey S., Murtskhvaladze M., Kotaria N., Schar T., Beisel C., Vugrek O., Rokic F., Trgovec-Greif L., Jurak I., Rukavina T., Sucic N., Schonning K., Karst S.M., Kirkegaard R.H., Michaelsen T.Y., Sorensen E.A., Knutson S., Brandt J., Le-Quy V., Sorensen T., Petersen C., Pedersen M.S., Larsen S.L., Skov M.N., Rasmussen M., Fonager J., Fomsgaard A., Maksyutov R.A., Gavrilova E.V., Pyankov O.V., Bodnev S.A., Tregubchak T.V., Shvalov A.N., Antonets D.V., Resende P.C., Goya S., Perrin A., Lee R.T., Yadahalli S., Han A.X., Russell C.A., Schmutz S., Zaheri M., Kufner V., Huber M., Trkola A., Antwerpen M., Walter M.C., van der Werf S., Gambaro F., Behillil S., Enouf V., Donati F., Ustinova M., Rovite V., Klovins J., Savicka O., Wienecke-Baldacchino A.K., Ragimbeau C., Fournier G., Mossong J., Aberle S.W., Haukland M., Enkirch T., Advani A., Karlberg M.L., Lindsjo O.K., Broddesson S., Slavikova M., Lickova M., Klempa B., Staronova E., Ticha E., Szemes T., Rusnakova D., Stadler T., Quer J., Anton A., Andres C., Pinana M., Garcia-Cehic D., Pumarola T., Izopet J., Gioula G., Exindari M., Papa A., Chatzidimitriou D., Metallidis S., Pappa S., Macek M., Geryk J., Broz P., Briksi A., Hubacek P., Drevinek P., Zajac M., Kvapil P., Holub M., Kvapilova K., Novotny A., Kasny M., Klempt P., Vapalahti O., Smura T., Sironen T., Selhorst P., Anthony C., Arien K., Simon-Loriere E., Rabalski L., Bienkowska-Szewczyk K., Borges V., Isidro J., Gomes J.P., Guiomar R., Pechirra P., Costa I., Duarte S., Vieira L., Pyrc K., Zuckerman N.S., Turdikulova S., Abdullaev A., Dalimova D., Abdurakhimov A., Tagliabracci A., Alessandrini F., Melchionda F., Onofri V., Turchi C., Bagnarelli P., Menzo S., Caucci S., Di Sante L., Popa A., Genger J.-W., Agerer B., Lercher A., Endler L., Smyth M., Penz T., Schuster M., Senekowitsch M., Laine J., Bock C., Bergthaler A., Shevtsov A., Kalendar R., Ramanculov Y., Graf A., Muenchhoff M., Keppler O.T., Krebs S., Blum H., Marcello A., Licastro D., D'Agaro P., Laubscher F., Vidanovic D., Tesovic B., Volkening J., Clementi N., Mancini N., Rupnik M., Mahnic A., Walker A., Houwaart T., Wienemann T., Vasconcelos M.K., Strelow D., Jensen B.-E.O., Senff T., Hulse L., Adams O., Andree M., Hauka S., Feldt T., Keitel V., Kindgen-Milles D., Timm J., Pfeffer K., Dilthey A.T., Moore C., Ozdarendeli A., Pavel S.T.I., Yetiskin H., Aydin G., Holyavkin C., Uygut M.A., Cevik C., Shchetinin A., Gushchin V., Dinler-Doganay G., Doganay L., Kizilboga-Akgun T., Karacan I., Pancer K., Maes P., Marti-Carreras J., Wawina-Bokalanga T., Vanmechelen B., Thurmer A., Wedde M., Durrwald R., von Kleist M., Drechsel O., Wolff T., Fuchs S., Kmiecinski R., Michel J., Nitsche A., Casas I., Caballero M.I., Zaballos A., Jimenez P., Jimenez M., Fernandez S.M., Fernandez S.V., de la Plaza I.C., Fadeev A., Ivanova A., Sergeeva M., Stefanelli P., Estee Torok M., Hall G., da Silva Filipe A., Turtle L., Afifi S., McCluggage K., Beer R., Ledesma J., Maksimovic J., Spellman K., Hamilton W.L., Marchbank A., Southgate J.A., Underwood A., Taylor B., Yeats C., Abudahab K., Gemmell M.R., Eccles R., Lucaci A., Nelson C.A., Rainbow L., Whitehead M., Gregory R., Haldenby S., Paterson S., Hughes M.A., Curran M.D., Baker D., Tucker R., Green L.R., Feltwell T., Halstead F.D., Wyles M., Jahun A.S., Ahmad S.S.Y., Georgana I., Goodfellow I., Yakovleva A., Meredith L.W., Gavriil A., Awan A.R., Fisher C., Edgeworth J., Lynch J., Moore N., Williams R., Kidd S.P., Cortes N., Brunker K., McCrone J.T., Quick J., Duckworth N., Walsh S., Sloan T., Ludden C., George R.P., Eltringham G., Brown J.R., Aranday-Cortes E., Shepherd J.G., Hughes J., Li K.K., Williams T.C., Johnson N., Jesudason N., Mair D., Thomson E., Shah R., Parr Y.A., Carmichael S., Robertson D.L., Nomikou K., Broos A., Niebel M., Smollett K., Tong L., Miah S., Wittner A., Phillips N., Payne B., Dewar R., Holmes A., Bolt F., Price J.R., Mookerjee S., Sethi D.K., Potter W., Stanley R., Prakash R., Dervisevic S., Graham J.C., Nelson A., Smith D., Young G.R., Yew W.C., Todd J.A., Trebes A., Andersson M., Bull M., Watkins J., Birchley A., Gatica-Wilcox B., Gilbert L., Kumziene-Summerhayes S., Rey S., Chauhan A., Butcher E., Bicknell K., Elliott S., Glaysher S., Lackenby A., Bibby D., Platt S., Mohamed H., Machin N.W., Mbisa J.L., Evans J., Perry M., Pacchiarini N., Corden S., Adams A.G., Gaskin A., Coombs J., Graham L.J., Cottrell S., Morgan M., Gifford L., Kolyva A., Rudder S.J., Trotter A.J., Mather A.E., Aydin A., Page A.J., Kay G.L., de Oliveira Martins L., Yasir M., Alikhan N.-F., Thomson N.M., Gilroy R., Kingsley R.A., O'Grady J., Gutierrez A.V., Diaz M., Viet T.L., Tedim A.P., Adriaenssens E.M., Patrick Mcclure C., Sang F., Clark G., Howson-Wells H.C., Debebe J., Ball J., Chappell J., Khakh M., Carlile M., Loose M., Lister M.M., Holmes N., Tsoleridis T., Fleming V.M., Wright V., Smith W., Gallagher M.D., Parker M., Partridge D.G., Evans C., Baker P., Essex S., Liggett S., Keeley A.J., Bashton M., Rooke S., Dervisavic S., Meader E.J., Lopez C.E.B., Angyal A., Kristiansen M., Tutill H.J., Findlay J., Mestek-Boukhibar L., Forrest L., Dyal P., Williams R.J., Panchbhaya Y., Williams C.A., Roy S., Pandey S., Stockton J., Loman N.J., Poplawski R., Nicholls S., Rowe W.P.M., Khokhar F., Pinckert M.L., Hosmillo M., Chaudhry Y., Caller L.G., Davidson R.K., Griffith L., Rambaut A., Jackson B., Colquhoun R., Hill V., Nichols J., Asamaphan P., Darby A., Jackson K.A., Iturriza-Gomara M., Vamos E.E., Green A., Aanensen D., Bonsall D., Buck D., Macintyre-Cockett G., de Cesare M., Pybus O., Golubchik T., Scarlett G., Loveson K.F., Robson S.C., Beckett A., Lindsey B., Groves D.C., Parsons P.J., McHugh M.P., Barnes J.D., Manso C.F., Grammatopoulos D., Menger K.E., Harrison E., Gunson R., Peacock S.J., Gonzalez G., Carr M., Mihaela L., Popovici O., Brytting M., Bresner C., Fuller W., Workman T., Mentis A.F., Kossyvakis A., Karamitros T., Pogka V., Kalliaropoulos A., Horefti E., Kontou A., Martinez-Gonzalez B., Labropoulou V., Voulgari-Kokota A., Evangelidou M., Bizta P., Belimezi M., Lambrechts L., Doymaz M.Z., Yazici M.K., Cetin N.S., Karaaslan E., Kallio-Kokko H., Virtanen J., Suvanto M., Nguyen P.T., Ellonen P., Hannula S., Kangas H., Sreenu V.B., Burian K., Terhes G., Gombos K., Gyenesei A., Urban P., Herczeg R., Jakab F., Kemenesi G., Toth G.E., Somogyi B., Zana B., Zeghbib S., Kuczmog A., Foldes F., Lanszki Z., Madai M., Papp H., Pereszlenyi C.I., Babinszky G.C., Dudas G., Csoma E., Abou Tayoun A.N., Alsheikh-Ali A.A., Loney T., Nowotny N., Abdul-Wahab O., Gonzalez-Candelas F., Andersen M.H., Taylor S., MARTI CARRERAS, Joan, Vanmechelen, Bert, Wawina, Tony, Medical Microbiology and Infection Prevention, AII - Infectious diseases, WHO European Region Sequencing Lab, GISAID EpiCoV Grp, Erik, Alm, Eeva K, Broberg, Thomas, Connor, Emma B, Hodcroft, Andrey B, Komissarov, Sebastian, Maurer-Stroh, Angeliki, Melidou, Richard A, Neher, Áine, O’Toole, Dmitriy, Pereyaslov, WHO European Region sequencing laboratories and GISAID EpiCoV group (Niko Beerenwinkel, The, Posada-Céspedes, Susana, Philipp, Kim, Jablonski, Falé Ferreira, Pedro, Topolsky, Ivan, Avšičžupanc, Tatjana, Korva, Miša, Poljak, Mario, Zakotnik, Samo, Tomaž, Zorec, Mark, Bragstad, Karoline, Hungnes, Olav, Stene-Johansen, Kathrine, Reusken, Chantal, Meijer, Adam, Vennema, Harry, Ruiz-Roldán, Lidia, Alma Bracho, María, García-González, Neri, Chiner-Oms, Álvaro, Cancino-Muñoz, Irving, Comas, Iñaki, A Goig, Galo, Torres-Puente, Manuela, G López, Mariana, Martínez-Priego, Llúcia, D’Auria, Giuseppe, LoretoFerrús-Abad, de Marco, Griselda, Galan-Vendrell, Inmaculada, Carbó-Ramirez, Sandra, Ruíz-Hueso, Paula, Coscollá, Mireia, Polackova, Katerina, Kramna, Lenka, Cinek, Ondrej, Richter, Jan, Krashias, George, Tryfonos, Christina, Bashiardes, Stavro, Koptides, Dana, Christodoulou, Christina, Bartolini, Barbara, Em Gruber, Cesare, Di Caro, Antonino, Castilletti, Concetta, Stefani, Fabrizio, Giordana Rimoldi, Sara, Romeri, Francesca, Salerno, Franco, Polesello, Stefano, Nagy, Alexander, Jirincova, Helena, Vecerova, Jaromira, Novakova, Ludmila, Cordey, Samuel, Murtskhvaladze, Marine, Kotaria, Nato, Schär, Tobia, Beisel, Christian, Vugrek, Oliver, Rokić, Filip, Trgovecgreif, Lovro, Jurak, Igor, Rukavina, Tomislav, Sučić, Neven, Schønning, Kristian, M Karst, Søren, H Kirkegaard, Rasmu, Y Michaelsen, Thoma, Aa Sørensen, Emil, Knutson, Simon, Brandt, Jakob, Le-Quy, Vang, Sørensen, Trine, Petersen, Celine, Schou Pedersen, Martin, Løkkegaard Larsen, Sanne, Nielsine Skov, Marianne, Rasmussen, Morten, Fonager, Jannik, Fomsgaard, Ander, Amirovich Maksyutov, Rinat, Vasil’Evna Gavrilova, Elena, Victorovich Pyankov, Oleg, Alexandrovich Bodnev, Sergey, Vladimirovna Tregubchak, Tatyana, Nikolayevich Shvalov, Alexander, Victorovich Antonets, Deni, Cristina Resende, Paola, Goya, Stephanie, Perrin, Amandine, Tc Lee, Raphael, Yadahalli, Shilpa, X Han, Alvin, A Russell, Colin, Schmutz, Stefan, Zaheri, Maryam, Kufner, Verena, Huber, Michael, Trkola, Alexandra, Antwerpen, Marku, C Walter, Mathia, van der Werf, Sylvie, Gambaro, Fabiana, Behillil, Sylvie, Enouf, Vincent, Donati, Flora, Ustinova, Monta, Rovite, Vita, Klovins, Jani, Savicka, Oksana, K Wienecke-Baldacchino, Anke, Ragimbeau, Catherine, Fournier, Guillaume, Mossong, Joël, W Aberle, Stephan, Haukland, Mattia, Enkirch, Theresa, Advani, Abdolreza, Lind Karlberg, Maria, Karlsson Lindsjö, Oskar, Broddesson, Sandra, Sláviková, Monika, Ličková, Martina, Klempa, Bori, Staroňová, Edita, Tichá, Elena, Szemes, Tomáš, Rusňáková, Diana, Stadler, Tanja, Quer, Josep, Anton, Andre, Andres, Cristina, Piñana, Maria, Garcia-Cehic, Damir, Pumarola, Toma, Izopet, Jacque, Gioula, Georgia, Exindari, Maria, Papa, Anna, Chatzidimitriou, Dimitrio, Metallidis, Symeon, Pappa, Stella, Macek Jr, Milan, Geryk, Jan, Brož, Petr, Briksí, Aleš, Hubáček, Petr, Dřevínek, Pavel, Zajac, Miroslav, Kvapil, Petr, Holub, Michal, Kvapilová, Kateřina, Novotný, Adam, Kašný, Martin, Klempt, Petr, Vapalahti, Olli, Smura, Teemu, Sironen, Tarja, Selhorst, Philippe, Anthony, Colin, Ariën, Kevin, Simon-Loriere, Etienne, Rabalski, Lukasz, Bienkowska-Szewczyk, Krystyna, Borges, Vítor, Isidro, Joana, Paulo Gomes, João, Guiomar, Raquel, Pechirra, Pedro, Costa, Inê, Duarte, Sílvia, Vieira, Luí, Pyrc, Krzysztof, S Zuckerman, Neta, Turdikulova, Shahlo, Abdullaev, Alisher, Dalimova, Dilbar, Abdurakhimov, Abror, Tagliabracci, Adriano, Alessandrini, Federica, Melchionda, Filomena, Onofri, Valerio, Turchi, Chiara, Bagnarelli, Patrizia, Menzo, Stefano, Caucci, Sara, Di Sante, Laura, Popa, Alexandra, Genger, Jakob-Wendelin, Agerer, Benedikt, Lercher, Alexander, Endler, Luka, Smyth, Mark, Penz, Thoma, Schuster, Michael, Senekowitsch, Martin, Laine, Jan, Bock, Christoph, Bergthaler, Andrea, Shevtsov, Alexandr, Kalendar, Ruslan, Ramanculov, Yerlan, Graf, Alexander, Muenchhoff, Maximilian, T Keppler, Oliver, Krebs, Stefan, Blum, Helmut, Marcello, Alessandro, Licastro, Danilo, D’Agaro, Pierlanfranco, Laubscher, Florian, Vidanovic, Dejan, Tesovic, Bojana, Volkening, Jeremy, Clementi, Nicola, Mancini, Nicasio, Rupnik, Maja, Mahnic, Aleksander, Walker, Andrea, Houwaart, Torsten, Wienemann, Tobia, Kohns Vasconcelos, Malte, Strelow, Daniel, Ole Jensen, Björn-Erik, Senff, Tina, Hülse, Lisanna, Adams, Ortwin, Andree, Marcel, Hauka, Sandra, Feldt, Torsten, Keitel, Verena, Kindgen-Milles, Detlef, Timm, Jörg, Pfeffer, Klau, T Dilthey, Alexander, Moore, Catherine, Ozdarendeli, Aykut, Terkis Islam Pavel, Shaikh, Yetiskin, Hazel, Aydin, Gunsu, Holyavkin, Can, Ali Uygut, Muhammet, Cevik, Ceren, Shchetinin, Alexey, Gushchin, Vladimir, Dinler-Doganay, Gizem, Doganay, Levent, Kizilboga-Akgun, Tugba, Karacan, Ilker, Pancer, Katarzyna, Maes, Piet, Martí-Carreras, Joan, Wawina-Bokalanga, Tony, Thürmer, Andrea, Wedde, Marianne, Dürrwald, Ralf, Von Kleist, Max, Drechsel, Oliver, Wolff, Thorsten, Fuchs, Stephan, Kmiecinski, Rene, Michel, Janine, Nitsche, Andrea, Casas, Inmaculada, Iglesias Caballero, María, Zaballos, Ángel, Jiménez, Pilar, Jiménez, Mercede, Monzón Fernández, Sara, Varona Fernández, Sarai, Cuesta De La Plaza, Isabel, Fadeev, Artem, Ivanova, Anna, Sergeeva, Mariia, Stefanelli, Paola, Estee Torok, M, Hall, Grant, da Silva Filipe, Ana, Turtle, Lance, Afifi, Safiah, Mccluggage, Kathryn, Beer, Robert, Ledesma, Juan, Maksimovic, Joshua, Spellman, Karla, L Hamilton, William, Marchbank, Angela, Alexander Southgate, Joel, Underwood, Anthony, Taylor, Ben, Yeats, Corin, Abudahab, Khalil, R Gemmell, Matthew, Eccles, Richard, Lucaci, Anita, Abigail Nelson, Charlotte, Rainbow, Lucille, Whitehead, Mark, Gregory, Richard, Haldenby, Sam, Paterson, Steve, A Hughes, Margaret, D Curran, Martin, Baker, David, Tucker, Rachel, R Green, Luke, Feltwell, Theresa, D Halstead, Fenella, Wyles, Matthew, S Jahun, Aminu, Y Ahmad, Shazaad S, Georgana, Iliana, Goodfellow, Ian, Yakovleva, Anna, W Meredith, Luke, Gavriil, Artemi, Raza Awan, Ali, Fisher, Chloe, Jonathan, European Centre for Disease Prevention and Control [Stockholm, Sweden] (ECDC), Cardiff University, Public Health Wales [Cardiff, Royaume uni], University of Basel (Unibas), Research Institute of Influenza, St. Petersburg, Russia, Agency for science, technology and research [Singapore] (A*STAR), National University of Singapore (NUS), University of Edinburgh, WHO Regional Office for Europe [Copenhagen], We gratefully acknowledge the authors, originating and submitting laboratories of the sequences from GISAID’s EpiCoV Database used in the phylogenetic analysis. We gratefully acknowledge all the staff working with sample collection, sample preparation, sequencing, data analysis and data sharing in all laboratories in the WHO European Region for making this work possible, The WHO European Region sequencing laboratories and GISAID EpiCoV group*: Niko Beerenwinkel, Susana Posada-Céspedes, Kim Philipp Jablonski, Pedro Falé Ferreira, Ivan Topolsky, Tatjana Avšič-Županc, Miša Korva, Mario Poljak, Samo Zakotnik, Tomaž Mark Zorec, Karoline Bragstad, Olav Hungnes, Kathrine Stene-Johansen, Chantal Reusken, Adam Meijer, Harry Vennema, Lidia Ruiz-Roldán, María Alma Bracho, Neris García-González, Álvaro Chiner-Oms, Irving Cancino-Muñoz, Iñaki Comas, Galo A Goig, Manuela Torres-Puente, Mariana G López, Llúcia Martínez-Priego, Giuseppe D'Auria, Paula Ruíz-Hueso, Loreto Ferrús-Abad, Griselda de Marco, Inmaculada Galan-Vendrell, Sandra Carbó-Ramirez, Paula Ruiz-Rodriguez, Mireia Coscollá, Katerina Polackova, Lenka Kramna, Ondrej Cinek, Jan Richter, George Krashias, Christina Tryfonos, Stavros Bashiardes, Dana Koptides, Christina Christodoulou, Barbara Bartolini, Cesare Em Gruber, Antonino Di Caro, Concetta Castilletti, Fabrizio Stefani, Sara Giordana Rimoldi, Francesca Romeri, Franco Salerno, Stefano Polesello, Alexander Nagy, Helena Jirincova, Jaromira Vecerova, Ludmila Novakova, Samuel Cordey, Marine Murtskhvaladze, Nato Kotaria, Tobias Schär, Christian Beisel, Oliver Vugrek, Filip Rokić, Lovro Trgovec-Greif, Igor Jurak, Tomislav Rukavina, Neven Sučić, Kristian Schønning, Søren M Karst, Rasmus H Kirkegaard, Thomas Y Michaelsen, Emil Aa Sørensen, Simon Knutson, Jakob Brandt, Vang Le-Quy, Trine Sørensen, Celine Petersen, Martin Schou Pedersen, Sanne Løkkegaard Larsen, Marianne Nielsine Skov, Morten Rasmussen, Jannik Fonager, Anders Fomsgaard, Rinat Amirovich Maksyutov, Elena Vasil'Evna Gavrilova, Oleg Victorovich Pyankov, Sergey Alexandrovich Bodnev, Tatyana Vladimirovna Tregubchak, Alexander Nikolayevich Shvalov, Denis Victorovich Antonets, Paola Cristina Resende, Stephanie Goya, Amandine Perrin, Raphael Tc Lee, Shilpa Yadahalli, Alvin X Han, Colin A Russell, Stefan Schmutz, Maryam Zaheri, Verena Kufner, Michael Huber, Alexandra Trkola, Markus Antwerpen, Mathias C Walter, Sylvie van der Werf, Fabiana Gambaro, Sylvie Behillil, Vincent Enouf, Flora Donati, Monta Ustinova, Vita Rovite, Janis Klovins, Oksana Savicka, Anke K Wienecke-Baldacchino, Catherine Ragimbeau, Guillaume Fournier, Joël Mossong, Stephan W Aberle, Mattias Haukland, Theresa Enkirch, Abdolreza Advani, Maria Lind Karlberg, Oskar Karlsson Lindsjö, Sandra Broddesson, Monika Sláviková, Martina Ličková, Boris Klempa, Edita Staroňová, Elena Tichá, Tomáš Szemes, Diana Rusňáková, Tanja Stadler, Josep Quer, Andres Anton, Cristina Andres, Maria Piñana, Damir Garcia-Cehic, Tomas Pumarola, Jacques Izopet, Georgia Gioula, Maria Exindari, Anna Papa, Dimitrios Chatzidimitriou, Symeon Metallidis, Stella Pappa, Milan Macek Jr, Jan Geryk, Petr Brož, Aleš Briksí, Petr Hubáček, Pavel Dřevínek, Miroslav Zajac, Petr Kvapil, Michal Holub, Kateřina Kvapilová, Adam Novotný, Martin Kašný, Petr Klempt, Olli Vapalahti, Teemu Smura, Tarja Sironen, Philippe Selhorst, Colin Anthony, Kevin Ariën, Etienne Simon-Loriere, Lukasz Rabalski, Krystyna Bienkowska-Szewczyk, Vítor Borges, Joana Isidro, João Paulo Gomes, Raquel Guiomar, Pedro Pechirra, Inês Costa, Sílvia Duarte, Luís Vieira, Krzysztof Pyrc, Neta S Zuckerman, Shahlo Turdikulova, Alisher Abdullaev, Dilbar Dalimova, Abror Abdurakhimov, Adriano Tagliabracci, Federica Alessandrini, Filomena Melchionda, Valerio Onofri, Chiara Turchi, Patrizia Bagnarelli, Stefano Menzo, Sara Caucci, Laura Di Sante, Alexandra Popa, Jakob-Wendelin Genger, Benedikt Agerer, Alexander Lercher, Lukas Endler, Mark Smyth, Thomas Penz, Michael Schuster, Martin Senekowitsch, Jan Laine, Christoph Bock, Andreas Bergthaler, Alexandr Shevtsov, Ruslan Kalendar, Yerlan Ramanculov, Alexander Graf, Maximilian Muenchhoff, Oliver T Keppler, Stefan Krebs, Helmut Blum, Alessandro Marcello, Danilo Licastro, Pierlanfranco D'Agaro, Florian Laubscher, Dejan Vidanovic, Bojana Tesovic, Jeremy Volkening, Nicola Clementi, Nicasio Mancini, Maja Rupnik, Aleksander Mahnic, Andreas Walker, Torsten Houwaart, Tobias Wienemann, Malte Kohns Vasconcelos, Daniel Strelow, Björn-Erik Ole Jensen, Tina Senff, Lisanna Hülse, Ortwin Adams, Marcel Andree, Sandra Hauka, Torsten Feldt, Verena Keitel, Detlef Kindgen-Milles, Jörg Timm, Klaus Pfeffer, Alexander T Dilthey, Catherine Moore, Aykut Ozdarendeli, Shaikh Terkis Islam Pavel, Hazel Yetiskin, Gunsu Aydin, Can Holyavkin, Muhammet Ali Uygut, Ceren Cevik, Alexey Shchetinin, Vladimir Gushchin, Gizem Dinler-Doganay, Levent Doganay, Tugba Kizilboga-Akgun, Ilker Karacan, Katarzyna Pancer, Piet Maes, Joan Martí-Carreras, Tony Wawina-Bokalanga, Bert Vanmechelen, Andrea Thürmer, Marianne Wedde, Ralf Dürrwald, Max Von Kleist, Oliver Drechsel, Thorsten Wolff, Stephan Fuchs, Rene Kmiecinski, Janine Michel, Andreas Nitsche, Inmaculada Casas, María Iglesias Caballero, Ángel Zaballos, Pilar Jiménez, Mercedes Jiménez, Sara Monzón Fernández, Sarai Varona Fernández, Isabel Cuesta De La Plaza, Artem Fadeev, Anna Ivanova, Mariia Sergeeva, Paola Stefanelli, M Estee Torok, Grant Hall, Ana da Silva Filipe, Lance Turtle, Safiah Afifi, Kathryn Mccluggage, Robert Beer, Juan Ledesma, Joshua Maksimovic, Karla Spellman, William L Hamilton, Angela Marchbank, Joel Alexander Southgate, Anthony Underwood, Ben Taylor, Corin Yeats, Khalil Abudahab, Matthew R Gemmell, Richard Eccles, Anita Lucaci, Charlotte Abigail Nelson, Lucille Rainbow, Mark Whitehead, Richard Gregory, Sam Haldenby, Steve Paterson, Margaret A Hughes, Martin D Curran, David Baker, Rachel Tucker, Luke R Green, Theresa Feltwell, Fenella D Halstead, Matthew Wyles, Aminu S Jahun, Shazaad S Y Ahmad, Iliana Georgana, Ian Goodfellow, Anna Yakovleva, Luke W Meredith, Artemis Gavriil, Ali Raza Awan, Chloe Fisher, Jonathan Edgeworth, Jessica Lynch, Nathan Moore, Rebecca Williams, Stephen P Kidd, Nicholas Cortes, Kirstyn Brunker, John T Mccrone, Joshua Quick, Nichola Duckworth, Sarah Walsh, Tim Sloan, Catherine Ludden, Ryan P George, Gary Eltringham, Julianne R Brown, Elihu Aranday-Cortes, James G Shepherd, Joseph Hughes, Kathy K Li, Thomas C Williams, Natasha Johnson, Natasha Jesudason, Daniel Mair, Emma Thomson, Rajiv Shah, Yasmin A Parr, Stephen Carmichael, David L Robertson, Kyriaki Nomikou, Alice Broos, Marc Niebel, Katherine Smollett, Lily Tong, Shahjahan Miah, Anita Wittner, Nicole Phillips, Brendan Payne, Rebecca Dewar, Alison Holmes, Frances Bolt, James R Price, Siddharth Mookerjee, Dheeraj K Sethi, Will Potter, Rachael Stanley, Reenesh Prakash, Samir Dervisevic, Jonathan Clive Graham, Andrew Nelson, Darren Smith, Gregory R Young, Wen Chyin Yew, John A Todd, Amy Trebes, Monique Andersson, Matthew Bull, Joanne Watkins, Alec Birchley, Bree Gatica-Wilcox, Lauren Gilbert, Sara Kumžiene-Summerhayes, Sara Rey, Anoop Chauhan, Ethan Butcher, Kelly Bicknell, Scott Elliott, Sharon Glaysher, Angie Lackenby, David Bibby, Steven Platt, Hodan Mohamed, Nicholas William Machin, Jean Lutamyo Mbisa, Jonathan Evans, Malorie Perry, Nicole Pacchiarini, Sally Corden, Alexander Geraint Adams, Amy Gaskin, Jason Coombs, Lee John Graham, Simon Cottrell, Mari Morgan, Laura Gifford, Anastasia Kolyva, Steven John Rudder, Alexander J Trotter, Alison E Mather, Alp Aydin, Andrew J Page, Gemma L Kay, Leonardo de Oliveira Martins, Muhammad Yasir, Nabil-Fareed Alikhan, Nicholas M Thomson, Rachel Gilroy, Robert A Kingsley, Justin O'Grady, Ana Victoria Gutierrez, Maria Diaz, Thanh Le Viet, Ana P Tedim, Evelien M Adriaenssens, C Patrick Mcclure, Christopher Moore, Fei Sang, Gemma Clark, Hannah C Howson-Wells, Johnny Debebe, Jonathan Ball, Joseph Chappell, Manjinder Khakh, Matthew Carlile, Matthew Loose, Michelle M Lister, Nadine Holmes, Theocharis Tsoleridis, Vicki M Fleming, Victoria Wright, Wendy Smith, Michael D Gallagher, Matthew Parker, David G Partridge, Cariad Evans, Paul Baker, Sarah Essex, Steven Liggett, Alexander J Keeley, Matthew Bashton, Stefan Rooke, Samir Dervisevic, Emma Jane Meader, Carlos Enrique Balcazar Lopez, Adrienn Angyal, Mark Kristiansen, Helena J Tutill, Jacqueline Findlay, Lamia Mestek-Boukhibar, Leysa Forrest, Patricia Dyal, Rachel J Williams, Yasmin Panchbhaya, Charlotte A Williams, Sunando Roy, Sarojini Pandey, Jo Stockton, Nicholas J Loman, Radoslaw Poplawski, Samuel Nicholls, W P M Rowe, Fahad Khokhar, Malte Lars Pinckert, Myra Hosmillo, Yasmin Chaudhry, Laura G Caller, Rose K Davidson, Luke Griffith, Andrew Rambaut, Ben Jackson, Rachel Colquhoun, Verity Hill, Jenna Nichols, Patawee Asamaphan, Alistair Darby, Kathryn A Jackson, Miren Iturriza-Gomara, Ecaterina Edith Vamos, Angie Green, David Aanensen, David Bonsall, David Buck, George Macintyre-Cockett, Mariateresa de Cesare, Oliver Pybus, Tanya Golubchik, Garry Scarlett, Katie F Loveson, Samuel C Robson, Angela Beckett, Benjamin Lindsey, Danielle C Groves, Paul J Parsons, Martin P Mchugh, James Daniel Barnes, Carmen F Manso, Dimitris Grammatopoulos, Katja Elisabeth Menger, Ewan Harrison, Rory Gunson, Sharon J Peacock, Gabriel Gonzalez, Michael Carr, Lazar Mihaela, Odette Popovici, Mia Brytting, Catherine Bresner, William Fuller, Trudy Workman, Andreas F Mentis, Athanasios Kossyvakis, Timokratis Karamitros, Vasiliki Pogka, Antonios Kalliaropoulos, Elina Horefti, Aspasia Kontou, Beatriz Martinez-Gonzalez, Voula Labropoulou, Androniki Voulgari-Kokota, Maria Evangelidou, Panagiota Bizta, Maria Belimezi, Laurens Lambrechts, Mehmet Z Doymaz, Merve Kalkan Yazici, Nesibe S Cetin, Elif Karaaslan, Hannimari Kallio-Kokko, Jenni Virtanen, Maija Suvanto, Phuoc Truong Nguyen, Pekka Ellonen, Sari Hannula, Harri Kangas, Vattipally B Sreenu, Katalin Burián, Gabriella Terhes, Katalin Gombos, Attila Gyenesei, Péter Urbán, Róbert Herczeg, Ferenc Jakab, Gábor Kemenesi, Gábor Endre Tóth, Balázs Somogyi, Brigitta Zana, Safia Zeghbib, Anett Kuczmog, Fanni Földes, Zsófia Lanszki, Mónika Madai, Henrietta Papp, Ágnes Nagy, Csaba István Pereszlényi, Gergely Csaba Babinszky, Gábor Dudás, Eszter Csoma, Ahmad N Abou Tayoun, Alawi A Alsheikh-Ali, Tom Loney, Norbert Nowotny, Osama Abdul-Wahab, Fernando Gonzalez-Candelas, Martin H Andersen, Sarah Taylor, Comas, Iñaki [0000-0001-5504-9408], Alm, E., Broberg, E. K., Connor, T., Hodcroft, E. B., Komissarov, A. B., Maurer-Stroh, S., Melidou, A., Neher, R. A., O'Toole, A., Pereyaslov, D., Beerenwinkel, N., Posada-Cespedes, S., Jablonski, K. P., Ferreira, P. F., Topolsky, I., Avsic-Zupanc, T., Korva, M., Poljak, M., Zakotnik, S., Zorec, T. M., Bragstad, K., Hungnes, O., Stene-Johansen, K., Reusken, C., Meijer, A., Vennema, H., Ruiz-Roldan, L., Bracho, M. A., Garcia-Gonzalez, N., Chiner-Oms, A., Cancino-Munoz, I., Comas, I., Goig, G. A., Torres-Puente, M., Lopez, M. G., Martinez-Priego, L., D'Auria, G., Ruiz-Hueso, P., Ferrus-Abad, L., de Marco, G., Galan-Vendrell, I., Carbo-Ramirez, S., Ruiz-Rodriguez, P., Coscolla, M., Polackova, K., Kramna, L., Cinek, O., Richter, J., Krashias, G., Tryfonos, C., Bashiardes, S., Koptides, D., Christodoulou, C., Bartolini, B., Gruber, C. E., Di Caro, A., Castilletti, C., Stefani, F., Rimoldi, S. G., Romeri, F., Salerno, F., Polesello, S., Nagy, A., Jirincova, H., Vecerova, J., Novakova, L., Cordey, S., Murtskhvaladze, M., Kotaria, N., Schar, T., Beisel, C., Vugrek, O., Rokic, F., Trgovec-Greif, L., Jurak, I., Rukavina, T., Sucic, N., Schonning, K., Karst, S. M., Kirkegaard, R. H., Michaelsen, T. Y., Sorensen, E. A., Knutson, S., Brandt, J., Le-Quy, V., Sorensen, T., Petersen, C., Pedersen, M. S., Larsen, S. L., Skov, M. N., Rasmussen, M., Fonager, J., Fomsgaard, A., Maksyutov, R. A., Gavrilova, E. V., Pyankov, O. V., Bodnev, S. A., Tregubchak, T. V., Shvalov, A. N., Antonets, D. V., Resende, P. C., Goya, S., Perrin, A., Lee, R. T., Yadahalli, S., Han, A. X., Russell, C. A., Schmutz, S., Zaheri, M., Kufner, V., Huber, M., Trkola, A., Antwerpen, M., Walter, M. C., van der Werf, S., Gambaro, F., Behillil, S., Enouf, V., Donati, F., Ustinova, M., Rovite, V., Klovins, J., Savicka, O., Wienecke-Baldacchino, A. K., Ragimbeau, C., Fournier, G., Mossong, J., Aberle, S. 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H., Taylor, S., European Centre for Disease Prevention and Control (ECDC), Public Health Wales Microbiology Cardiff, Faculty of Agriculture and Forestry, Department of Agricultural Sciences, and Institute of Biotechnology

Subjects
Infecções Respiratórias, 0301 basic medicine, MESH: Coronavirus Infections, Epidemiology, [SDV]Life Sciences [q-bio], Distribution (economics), Wastewater, MESH: Base Sequence, Severe Acute Respiratory Syndrome, MESH: World Health Organization, Pandemic, MESH: Coronavirus, MESH: COVID-19, Sequencing, Viral, Clade, Nomenclature, Genome, biology, COVID-19, Europe, NGS, SARS-CoV-2, WGS, nomenclature, sequencing, Base Sequence, Betacoronavirus, Coronavirus, Coronavirus Infections, Genome, Viral, Humans, Phylogeography, Pneumonia, Viral, RNA, Viral, RNA-Dependent RNA Polymerase, Spatio-Temporal Analysis, World Health Organization, Pandemics, C500, European region, 3. Good health, Geography, MESH: Phylogeography, MESH: RNA-Dependent RNA Polymerase, MESH: RNA, Viral, MESH: Betacoronavirus, Spatio-Temporal Analysi, MESH: Genome, Viral, Cartography, Human, Bioquímica, MESH: Pandemics, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Coronaviru, 030106 microbiology, 03 medical and health sciences, MESH: Spatio-Temporal Analysis, MESH: Severe Acute Respiratory Syndrome, Virology, MESH: SARS-CoV-2, Whole genome sequencing, MESH: Humans, Whole Genome Sequencing, Betacoronaviru, Coronavirus Infection, business.industry, Public Health, Environmental and Occupational Health, Pneumonia, biology.organism_classification, B900, 030104 developmental biology, MESH: Pneumonia, Viral, RNA, SARS_CoV-2, 3111 Biomedicine, MESH: Europe, Human medicine, business
Abstract

8 páginas, 3 figuras, We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2., We gratefully acknowledge the authors, originating and submitting laboratories of the sequences from GISAID’s EpiCoV Database used in the phylogenetic analysis. We gratefully acknowledge all the staff working with sample collection, sample preparation, sequencing, data analysis and data sharing in all laboratories in the WHO European Region for making this work possible.

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25. Other autoinflammatory disease genes in an FMF-prevalent population: a homozygous MVK mutation and a novel heterozygous TNFRSF1A mutation in two different Turkish families with clinical FMF.

Author

Karacan İ, Uğurlu S, Tolun A, Tahir Turanlı E, and Ozdogan H

Subjects
Adolescent, Child, DNA Mutational Analysis, Diagnosis, Differential, Familial Mediterranean Fever diagnosis, Familial Mediterranean Fever epidemiology, Familial Mediterranean Fever immunology, Female, Fever diagnosis, Fever epidemiology, Fever immunology, Genetic Predisposition to Disease, Hereditary Autoinflammatory Diseases diagnosis, Hereditary Autoinflammatory Diseases epidemiology, Hereditary Autoinflammatory Diseases immunology, Heredity, Humans, Male, Mevalonate Kinase Deficiency diagnosis, Mevalonate Kinase Deficiency epidemiology, Mevalonate Kinase Deficiency immunology, Middle Aged, Pedigree, Phenotype, Predictive Value of Tests, Prevalence, Pyrin genetics, Risk Factors, Turkey epidemiology, Young Adult, Familial Mediterranean Fever genetics, Fever genetics, Hereditary Autoinflammatory Diseases genetics, Heterozygote, Homozygote, Mevalonate Kinase Deficiency genetics, Mutation, Missense, Nerve Tissue Proteins genetics, Phosphotransferases (Alcohol Group Acceptor) genetics
Abstract

Objectives: No MEFV mutations are detected in approximately 10% of the patients with clinical FMF in populations where the disease is highly prevalent. Causative mutations were searched in other genes in two such families with "MEFV negative clinical FMF"., Methods: Father and daughter of family A had attacks of fever, abdominal pain and AA amyloidosis. The two sibs of family B complained of febrile episodes with abdominal pain and arthritis. The patients were clinically investigated. Exome analysis in the daughter in family A and linkage analysis and candidate gene sequencing for the members of family B were performed. All patients were re-evaluated in the light of the genetic findings., Results: In the daughter in family A, filtering of the exome file for variants in 25 autoimmune/inflammatory disease-related genes revealed two heterozygous missense variants in TNFRSF1A, novel p.Cys72Phe and frequent p.Arg121Gln. In family B, novel, homozygous missense p.Cys161Arg in MVK was identified. A clinical re-evaluation of the patients revealed a phenotype consistent with FMF rather than TRAPS in family A and an overlap of FMF with HIDS in family B., Conclusions: In high risk populations of FMF a proportion of patients without MEFV mutations may carry causative mutations in other genes, and the clinical findings may not be fully consistent with the phenotype expected of the mutation identified but rather resemble FMF or an overlap syndrome.

Published
2017

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