Retrospective analysis of persistent HyperCKemia with or without muscle weakness in a case series from Greece highlights vast DMD variant heterogeneity

ABSTRACT

Background

Persistent hyperCKemia results from muscle dysfunction often attributed to genetic alterations of muscle-related genes, such as the dystrophin gene (DMD). Retrospective assessment of findings from DMD analysis, in association with persistent HyperCKemia, was conducted.

Patients and methods

Evaluation of medical records from 1354 unrelated cases referred during the period 1996–2021. Assessment of data concerning the detection of DMD gene rearrangements and nucleotide variants.

Results

A total of 730 individuals (657 cases, 569 of Greek and 88 of Albanian origins) were identified, allowing an overall estimation of dystrophinopathy incidence at ~1:3800 live male births. The heterogeneous spectrum of 275 distinct DMD alterations comprised exon(s) deletions/duplications, nucleotide variants, and rare events, such as chromosome translocation {t(X;20)}, contiguous gene deletions, and a fused gene involving the DMD and the DOCK8 genes. Ethnic-specific findings include a common founder variant in exon 36 (‘Hellenic’ variant).

Conclusions

Some 50% of hyperCKemia cases were characterized as dystrophinopathies, highlighting that DMD variants may be considered the most common cause of hyperCKemia in Greece. Delineation of the broad genetic and clinical heterogeneity is fundamental for actionable public health decisions and theragnosis, as well as the establishment of guidelines addressing ethical considerations, especially related to the mild asymptomatic patient subgroup.

KEYWORDS:

• Dystrophin
• Duchenne
• creatine kinase
• hyperCKemia case series
• epidemiology

Abreviations

ACMG	=	American College of Medical Genetics
BMD	=	Becker Muscular Dystrophy
CK	=	Creatine Kinase
CYBB	=	Cytochrome b(-245), beta subunit
CNV	=	Copy Number Variants (Variations)
DCM	=	Dilated CardioMyopathy
DMD	=	Duchenne Muscular dystrophy
DOCK8	=	Dedicator Of Cytokinesis 8
DOVE	=	DMD Open Variant Explorer
EFNS	=	European Federation of Neurological Societies
FMR1	=	Fragile X Messenger Ribonucleoprotein 1 gene
HUMARA	=	HUMan Androgen Receptor Assay
LMG	=	Laboratory of Medical Genetics
MLPA	=	Multiplex Ligation-dependent Probe Amplification
NGS	=	Next-Generation Sequencing
ULN	=	Upper Limit of the Normal range
SNV	=	Single Nucleotide Variants (Variations)
XCI	=	X-Chromosome Inactivation

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

K Kekou conceptualized the study, performed retrospective analysis of data including variant analysis and interpretation, and drafted the article. M Svingou and N Vogiatzakis performed data analysis, genetic interpretation, and RNA studies. E Nitsa is responsible for the statistical analysis. D Veltra performed X-inactivation studies and respective findings evaluation. N Marinakis and F-N Tilemis performed WES analysis including variant and CNVs characterization and evaluation. C Tsaroucha and N Selenti performed cytogenetic studies and karyotyping. M Tzetis and A Mitrakos performed a-CGH analysis and respective data evaluation. G-K Papadimas and C Papadopoulos performed muscle biopsies and respective data interpretation. J Traeger-Synodinos supervised the study and revised the manuscript. H Lochmuller critically revised the study and the manuscript. C Sofocleous participated in the conceptualization and supervision of the study, the interpretation of data, and the preparation of the manuscript.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethical publication statement

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Acknowledgments

The authors would like to thank all patients, their families, as well as the technician Mrs Sophia Vretta and the nurse Mrs Konstantina Gerasimidou. The authors acknowledge the contribution of Dr Lina Florentin in the establishment of dystrophinopathies genetic analysis in the Laboratory of Medical Genetics, and the Emeritus Professors Ekaterini Metaxotou and Emmanuel Kanavakis for their valuable support. We would also like to thank the clinicians: M. Arnaoutoglou, E. Chroni, E. Dardiotis, N. Diamantopoulos, S. Giouroukos, A. Gkika, D. Gouga, A. Evangeliou, A. Katerelos, M. Katsalouli, V.K. Kimiskidis, Ch. Kotsalis, V. Koute, E. Lykopoulou, M. Μoschou, S. Mouskou, I. Nakou, G. Niotakis, A. Dinopoulos, A. Papavasileiou, P. Pelekouda, K. Skiadas. E. Pavlou, K. Voudris, K. Kosma, E. Pavlidou, R. Pons, I. Sarmas. Ε. Tsoutsou, E. Skouteli, G. Tsivgoulis, G. Vartzelis, and P. Vorgia, for the referrals.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14737159.2023.2264181

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.