Genetic Landscape of Dystrofin Gene Deletions and Duplications From Turkey: A Single Center Experience

Abstract

Objective: Dystrophinopathies are the most frequently researched neuromuscular disease group due to their characteristic and diverse clinical and genetic spectrum. This study aims to evaluate the deletion and duplication profile of the dystrophin gene in Turkey by investigating data from a tertiary center.

Material and Methods: Dystrophin MLPA and microarray results of 53 patients, 49 with a dystrophinopathy and 4 with a neurogenetic and syndromic disorder pre-diagnosis, who were referred to the Medical Genetics Clinic of Ankara City Hospital between February 2019-December 2020 were retrospectively evaluated.

Results: Of the 53 patients, 4 had various exon duplications and 49 had deletions. 33 of these mutations caused frame-shift (62.3%), while 20 caused in-frame (37.7%) changes. Fifty (94.3%) patients underwent maternal studies and 14 (26.4%) of these had de novo mutations. Mutations were observed most frequently in the central rod domain (69.7%) followed by the actin-binding domain (7.5%) of the dystrophin gene and 12 of 33 patients with frameshift mutation (36%) patients were found to be candidates for the exon skipping treatments that are still subject to clinical research.

Conclusion: This study has shed light on the incidence of dystrophin deletion/duplication mutations in our population and has revealed that a majority of patients are suitable candidates for treatments which are still not in routine use. Considering ever-growing number of dystrophin gene-based treatment options, data on population-specific mutation types is of great importance.

Keywords

• Deletion/duplication
• Duchenne Muscular Dystrophy
• MLPA
• Exon skipping

Distrofin Genindeki Delesyon ve Duplikasyonların Türkiye’deki Profili: Tek Merkez Deneyimi

Abstract

Amaç: Distrofinopatiler; kendilerine özgü ve oldukça geniş klinik ve genetik spektrumu ile nöromusküler hastalıklar içinde halen en sık araştırma konusu olan gruptur. Bu araştırmada bir merkezden elde edilen sonuçlar değerlendirilerek Türkiye’deki distrofin geni delesyon ve duplikasyon profilinin ortaya konulması amaçlanmıştır.

Gereç ve Yöntemler: Ankara Şehir Hastanesi Tıbbi Genetik Polikliniği’ne Şubat 2019-Aralık 2020 tarihleri arasında 49’u distrofinopati, 4’ü nörogenetik-sendromik bozukluklar klinik ön tanısı ile yönlendirilen 53 hastaya ait distrofin MLPA ve mikrodizin sonuçları retrospektif olarak değerlendirildi.

Bulgular: Çalışmaya alınan 53 hastanın 4’ünde distrofin geninde çeşitli ekzon duplikasyonları saptanmış olup kalan 49 hastada delesyon olduğu görüldü. Bu mutasyonların 33’ü frame-shift (%62.3), 20’si in-frame (%37.7) değişikliğe neden olmaktadır. Maternal çalışma yapılan 50 hasta (%94.3) değerlendirildiğinde 14 hastada (%26.4) de novo mutasyon olduğu görüldü. Distrofin geninde en sık santral rod domain’de (%69.7), ikinci sıklıkla aktin bağlayıcı bölümde (%7.5) mutasyonlar izlenmiştir. Henüz klinik araştırmaları devam eden güncel ekzon atlatma tedavileri açısından çerçeve kayması tipi mutasyona sahip 33 hastanın 12’sinin (%36) aday olduğu saptandı.

Sonuç: Bu çalışma ile popülasyonumuz açısından distrofin delesyon/duplikasyon mutasyon sıklıklarına ışık tutulmuş ve henüz rutin kullanıma girmeyen tedaviler açısından dahi hastaların önemli bir kısmının aday olduğu tespit edilmiştir. Son yıllarda gelişen distrofin geni temelli tedavi olanakları da göz önünde tutulursa populasyonlara ait mutasyon tipi sıklıklarının bilinmesi büyük önem taşımaktadır.

Keywords

• Delesyon/duplikasyon,
• Duchenne musküler distrofi
• MLPA
• Ekzon atlama

References

1. 1- Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, et al. DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17:251-67.
2. 2- Birnkrant DJ, Bushby K, Bann CM, Alman BA, Apkon SD, Blackwell A, et al. DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol. 2018;17:347-61.
3. 3- Aartsma-Rus A, Ginjaar IB, Bushby K. The importance of genetic diagnosis for Duchenne muscular dystrophy. Journal of Medical Genetics.2016;53:145-51.
4. 4- Datta N, Ghosh PS. Update on Muscular Dystrophies with Focus on Novel Treatments and Biomarkers.Curr Neurol Neurosci Rep. 2020;14;20:14.
5. 5- Selvatici R, Rossi R, Fortunato F, Trabanelli C, Sifi Y, Margutti A, et al. Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries. Neurol Genet. 2020;24;7:e536.
6. 6- Yang YM, Yan K, Liu B, Chen M, Wang LY, Huang YZ, et al. Comprehensive genetic diagnosis of patients with Duchenne/Becker muscular dystrophy (DMD/BMD) and pathogenicity analysis of splice site variants in the DMD gene. J Zhejiang Univ Sci B. 2019;20:753-65.
7. 7- Tuffery-Giraud S, Béroud C, Leturcq F, Yaou RB, Hamroun D, Michel-Calemard L, et al. Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase. Hum Mutat. 2009;30:934-45
8. 8- Lim KRQ, Nguyen Q, Yokota T. Genotype-Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry. J Pers Med. 2020;23;10:241

9. 9- Neri M, Rossi R, Trabanelli C, Mauro A, Selvatici R, Falzarano MS, et al. The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study. Front Genet. 2020; 3;11:131
10. 10- Topaloğlu H. Neuromuscular disorders in Anatolia - A personal review. Neuromuscul Disord. 2019;29:152-56
11. 11- Toksoy G, Durmus H, Aghayev A, Bagirova G, Sevinc Rustemoglu B, Basaran S, et al. Mutation spectrum of 260 dystrophinopathy patients from Turkey and important highlights for genetic counseling. Neuromuscul Disord. 2019;29:601-13
12. 12- Bektaş G , Başkent G , Ulak Özkan M , Pembegül Yıldız E , Aydınlı N , Çalışkan M, et al. Duchenne Musküler Distrofili Çocuklarda Genotip-Fenotip İlişkisi: Tek Merkez Deneyimi. Türkiye Çocuk Hast Derg. 2020;14: 518-21
13. 13- Kohli S, Saxena R, Thomas E, Singh K, Bijarnia Mahay S, Puri RD, et al. Mutation Spectrum of Dystrophinopathies in India: Implications for Therapy. Indian J Pediatr. 2020;87:495-504
14. 14- Sun C, Shen L, Zhang Z, Xie X. Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update. Genes. 2020;23;1:837
15. 15- Cure Duchenne. Available from: https://www.cureduchenne.org/wp-content/uploads/2016/11/Duchenne-Population-Potentially-Amenable-to-Exon-Skipping-11.10.16.pdf
16. 16- Mathur P, Agarwal A, Goyal K, Mathur, A. Mutation spectrum of Duchenne muscular dystrophy patients in Indian population. Indian Journal of Child Health. 2020; 7; 247-50
17. 17- Ceylan AC, Citli S, Erdem HB, Sahin I, Arslan EA, et al. Importance and usage of chromosomal microarray analysis in diagnosing intellectual disability, global developmental delay, and autism; and discovering new loci for these disorders. Molecular cytogenetics. 2018; 11; 1-9
18. 18- Le Rumeur, E. Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies. Bosn. J. Basic Med. Sci. 2015;15;14–20
19. 19- Mias-Lucquin D, Dos Santos Morais R, Chéron A, Lagarrigue M, Winder, S.J, et al. How the central domain of dystrophin acts to bridge F-actin to sarcolemmal lipids. J. Struct. Biol. 2020;209;107411.
20. 20- Ma P, Zhang S, Zhang H, Fang S, Dong Y, Zhang Y, Hao W, Wu S, Zhao Y. Comprehensive genetic characteristics of dystrophinopathies in China. Orphanet J Rare Dis. 2018;4;13:109