Chromosome 4q D4Z4 contraction status in Turkish patients with facioscapulohumeral muscular dystrophy

Year 2025, Volume: 50 Issue: 3, 702 - 711, 30.09.2025

Ceren Hangül , Özge Burcu Şahan , Sibel Karaüzüm , Elizabeta Sauer , Hilmi Uysal , Filiz Koç

https://doi.org/10.17826/cumj.1736413

Abstract

Purpose: This study aimed to provide an updated overview of the genetic and clinical features of patients with facioscapulohumeral muscular dystrophy1 (FSHD1) followed between 2006 and 2025 in the Mediterranean region of Turkey.
Materials and Methods: A total of 46 patients diagnosed as having FSHD1 through Southern blot analysis were included. The cohort consisted of 26 males and 20 females, with a mean age of 32.93 ± 17.01 years. Clinical severity scores (CSS) and age-corrected CSS (ACSS) were assessed based on neurologic examinations.
Results: The most frequent D4Z4 repeat size was 4 units (30.4%). Although CSS and ACSS appeared lower in female patients, the difference was not statistically significant. Patients aged under 30 years exhibited significantly lower CSS and ACSS compared with those aged over 30 years. A strong correlation was observed between age and both CSS and ACSS; no significant correlation was found between D4Z4RU and clinical severity. Among the 46 patients, 20 families were represented, and one patient had a de novo mosaic mutation.
Conclusion: Our findings highlight the importance of longitudinal and population-specific data in understanding FSHD. Increased molecular diagnosis and regular follow-up of patients may facilitate future research and the development of targeted therapies.

Keywords

Facioscapulohumeral Muscular Dystrophy , FSHD1 , Southern Blot , D4Z4 repeat contraction , Genotype phenotype correlation , Clinical Severity , Diagnosis , 4qter

Ethical Statement

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Supporting Institution

Akdeniz University and Cukurova University

Türk fasiyoskapulohumeral müsküler distrofi hastalarında kromozom 4q D4Z4 kontraksiyon durumu

Abstract

Amaç: Bu çalışmada, 2006–2025 yılları arasında Türkiye’nin Akdeniz bölgesinde takip edilen Fasiyoskapulohumeral müsküler distrofi 1 (FSHD1) hastalarının genetik ve klinik özelliklerine dair güncel bir değerlendirme sunulması amaçlanmıştır.
Gereç ve Yöntem: Southern blot analizi ile FSHD1 tanısı alan toplam 46 hasta çalışmaya dahil edilmiştir. Kohort, yaş ortalaması 32,93 ± 17,01 yıl olan 26 erkek ve 20 kadından oluşmaktadır. Klinik Şiddet Skoru (CSS) ve yaşa göre düzeltilmiş CSS (ACSS), nörolojik muayeneler temelinde değerlendirilmiştir.
Bulgular: En sık gözlenen D4Z4 tekrar sayısı 4 olup, hastaların %30,4’ünde saptanmıştır. Kadın hastalarda CSS ve ACSS değerleri daha düşük görünmekle birlikte, bu fark istatistiksel olarak anlamlı bulunmamıştır. 30 yaş altındaki hastalarda CSS ve ACSS değerleri, 30 yaş üzerindekilere kıyasla anlamlı düzeyde daha düşük bulunmuştur. Yaş ile hem CSS hem de ACSS arasında güçlü bir pozitif korelasyon gözlenmiştir, buna karşın D4Z4RU ile klinik şiddet arasında anlamlı bir ilişki saptanmamıştır. Kohortta 20 farklı aile yer almakta olup, bir olguda mozaik yapıda de novo mutasyon tespit edilmiştir.
Sonuç: Elde edilen bulgular, FSHD'nin daha iyi anlaşılabilmesi için longitudinal ve popülasyona özgü verilere duyulan ihtiyacı vurgulamaktadır. Moleküler tanı oranlarının artırılması ve hastaların düzenli takibi, gelecekteki araştırmaların ve hedefe yönelik tedavi stratejilerinin geliştirilmesine katkı sağlayabilir.

Keywords

Fasioskapulohumeral Kas Distrofisi , FSHD1 , Southern Blot , D4Z4 tekrar kasılması , Genotip fenotip korelasyonu , Klinik Şiddet , Tanı , 4qter

References

• Lunt PW, Harper PS. Genetic counselling in facioscapulohumeral muscular dystrophy. J Med Genet. 1991;28:655-64.
• Wang Z, Qiu L, Lin M, Chen L, Zheng F, Lin L et al. Prevalence and disease progression of genetically-confirmed facioscapulohumeral muscular dystrophy type 1 (FSHD1) in China between 2001 and 2020: a nationwide population-based study. Lancet Reg Health West Pac. 2022;18:100323.
• Mostacciuolo ML, Pastorello E, Vazza G, Miorin M, Angelini C, Tomelleri G et al. Facioscapulohumeral muscular dystrophy: Epidemiological and molecular study in a north-east Italian population sample. Clin Genet. 2009;75:550-5.
• Winnen A, Srivastsa S, Eldar-Lissai A, Kouchlev I, Jones G, Zuroske T. EPH75 applying machine learning (ml) to estimate prevalence of facioscapulohumeral muscular dystrophy (fshd) and related disease burden: findings from United States claims analysis. Value in Health; 2022;25(Suppl 12):S205–6.
• Wijmenga C, Sandkuijl LA, Moerer P, Van Der Boorn N, Bodrug SE, Ray PN et al. Genetic linkage map of facioscapulohumeral muscular dystrophy and five polymorphic loci on chromosome 4q35-qter. Am J Hum Genet. 1992;51:411-5.
• Lemmers RJLF, Tawil R, Petek LM, Balog J, Block GJ, Santen GWE et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012;44:1370-4.
• Van Den Boogaard ML, Lemmers RJLF, Balog J, Wohlgemuth M, Auranen M, Mitsuhashi S et al. Mutations in dnmt3b modify epigenetic repression of the d4z4 repeat and the penetrance of facioscapulohumeral dystrophy. Am J Hum Genet. 2016;98:1020-29.
• Hamanaka K, Šikrová D, Mitsuhashi S, Masuda H, Sekiguchi Y, Sugiyama A et al. Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy. Neurology. 2020;94:e2441-e2447.
• Thomas NST, Wiseman K, Spurlock G, MacDonald M, Üstek D, Upadhyaya M. A large patient study confirming that facioscapulohumeral muscular dystrophy (FSHD) disease expression is almost exclusively associated with an FSHD locus located on a 4qA-defined 4qter subtelomere. J Med Genet. 2007;44:215-8.
• Hewitt JE, Lyle R, Clark LN, Valleley EM, Wright TJ, Wijmenga C et al. Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystropothhy. Hum Mol Genet. 1994;3:1287-95.
• Şahan ÖB. Fasioskapulohumeral musküler distrofili olgularda 4q`35`te lokalize D4Z4 tekrar dizilerindeki delesyonların gösterilmesi. Antalya, Akdeniz University Faculty of Medicine. 2012.
• Hangül C, Bozkurt S, Bilge U, Özdem S, Altunbaş H, Uysal H et al. The ratios of estradiol and progesterone to testosterone influence the severity of facioscapulohumeral muscular dystrophy. Neurol Sci Neurophysiol. 2020;37:190-6.
• Ricci E, Galluzzi G, Deidda G, Cacurri S, Colantoni L, Merico B et al. Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann Neurol. 1999;45:751-7.
• Van Overveld PGM, Enthoven L, Ricci E, Rossi M, Felicetti L, Jeanpierre M et al. Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy. Ann Neurol. 2005;58:569-76.
• Tonini MMO, Passos-Bueno MR, Cerqueira A, Matioli SR, Pavanello R, Zatz M. Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD). Neuromuscular Disorders. 2004;14:33-8.
• Zatz M, Marie SK, Cerqueira A, Vainzof M, Pavanello RCM, Passos-Bueno MR. The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Am J Med Genet. 1998;77:155-61.
• Lamperti C, Fabbri G, Vercelli L, D’Amico R, Frusciante R, Bonifazi E et al. A standardized clinical evaluation of patients affected by facioscapulohumeral muscular dystrophy: The FSHD clinical score. Muscle Nerve. 2010;42:213-7.
• Hatch MN, Kim K, Kurillo G, Nicorici A, McDonald CM, Han JJ. Longitudinal study of upper extremity reachable workspace in fascioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2019;29:503-513.
• Hangul C, Ozsoy U, Hizay A, Karauzum SB, Sauer E, Firat MZ et al. Quantitative three-dimensional scanning of facial movements in facioscapulohumeral dystrophy. Neurol Sci Neurophysiol. 2025;42:48–55.
• Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy: Molecular pathological advances and future directions. Curr Opin Neurol. 2011:24:423-8.
• Tawil R, Forrester J, Griggs RC, Mendell J, Kissel J, McDermott M et al. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular systrophy. Ann Neurol. 1996;39:744-8.
• Statland JM, Donlin-Smith CM, Tapscott SJ, Lemmers RJLF, Van Der Maarel SM, Tawil R. Milder phenotype in facioscapulohumeral dystrophy with 7-10 residual D4Z4 repeats. Neurol. 2015;85:2147-50.
• Klinge L, Eagle M, Haggerty ID, Roberts CE, Straub V, Bushby KM. Severe phenotype in infantile facioscapulohumeral muscular dystrophy. Neuromuscular Disorders. 2006;16:553-8.
• Butz M, Koch MC, Müller-Felber W, Lemmers RJLF, Van Der Maarel SM, Schreiber H. Facioscapulohumeral muscular dystrophy: Phenotype-genotype correlation in patients with borderline D4Z4 repeat numbers. J Neurol. 2003;250:932-7.
• Van Overveld PGM, Lemmers RJFL, Sandkuijl LA, Enthoven L, Winokur ST, Bakels F et al. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet. 2003;35:315-7.
• Yunisova G, Eraslan S, Avci S, Eren İ, Demirhan M, Kayserili H et al. Clinical and molecular characteristics of patients with fascio-scapulo-humeral dystrophy 1 (fshd 1): the first cohort investigating the genotype-phenotype characteristics of fshd 1 patients in turkey (P3-11.019). Neurol. 2024:P3-11.019.
• Erdmann H, Scharf F, Gehling S, Benet-Pagès A, Jakubiczka S, Becker K et al. Methylation of the 4q35 D4Z4 repeat defines disease status in facioscapulohumeral muscular dystrophy. Brain. 2023;146:1388-1402.
• Hangul C, Celik EG, Kaya H, Eroglu O, Uysal H, Karauzum SB. Estradiol differentially regulates DUX4, β-catenin and PAX3/PAX7 in primary myoblasts of facioscapulohumeral muscular dystrophy patients. Turk Biyokim Derg. 2021;46:435-44.
• Hangul Ceren, Ozcan Filiz, Darbas Sule, Uysal Hilmi, Koc Filiz Ayse, Karauzum Berker Sibel. Progesterone may be a regulator and B12 could be an indicator of the proximal D4Z4 repeat methylation status on 4q35ter. J Neurochem. 2024;168:3209–20.
• Nguyen K, Walrafen P, Bernard R, Attarian S, Chaix C, Vovan C et al. Molecular combing reveals allelic combinations in facioscapulohumeral dystrophy. Ann Neurol. 2011;70:627-33.
• Chun Pang AW, Hastie A, Chaubey A. Identification of structural variation in constitutional disorders by optical genome mapping. Mol Genet Metab. 2021;132:S281.
• Mitsuhashi S, Nakagawa S, Takahashi Ueda M, Imanishi T, Frith MC, Mitsuhashi H. Nanopore-based single molecule sequencing of the D4Z4 array responsible for facioscapulohumeral muscular dystrophy. Sci Rep. 2017;7:14789.
• Hangül C, Karaüzüm SB, Akkol EK, Demir-Dora D, Çetin Z, Saygılı Eİ et al. Promising perspective to facioscapulohumeral muscular dystrophy treatment: nutraceuticals and phytochemicals. Curr Neuropharmacol. 2021;19:2276-95.
• Akpınar A, Gözke E. Evaluation of the relationship between Fascioscapulohumeral dystrophy and noonan syndrome. Neurol Sci Neurophysiol. 2025;42:69–71.
• Hangül C, Yücel OK, Toylu A, Uysal H, Karaüzüm SB. A novel coincidence: essential thrombocythemia with facioscapulohumeral muscular dystrophy. Turk J Haematol. 2020;37:306-7.
• Hangul C, Tokta O, Karauzum SB, Akkaya B, Yildirim H, Kupesiz FT et al. Analysis of dux4 expression in bone marrow and re-discussion of dux4 function in the health and disease. Turk Patoloji Derg. 2021;38:219–26.
• Ragozzino E, Bortolani S, Di Pietro L, Papait A, Parolini O, Monforte M et al. Muscle fibrosis as a prognostic biomarker in facioscapulohumeral muscular dystrophy: a retrospective cohort study. Acta Neuropathol Commun. 2023;11:165.