Inherited myopathies and congenital myasthenic syndromes: insights from a turkish cohort

Introduction

Hereditary myopathies (MYO) and congenital myasthenic syndromes (CMS) are heterogeneous groups of disorders characterized by a broad spectrum of clinical severity and variable disease courses. Both conditions affect a substantial number of individuals worldwide, with prevalence varying according to age, sex, ethnicity, and underlying genetic etiology. These disorders are often associated with significant diagnostic challenges due to overlapping clinical and genetic features. Turkey, with its wide geographical distribution and relatively high rate of consanguinity, presents a unique population structure with increased genetic diversity.

Aims

This study aims to investigate the genetic basis of MYO and CMS in a Turkish cohort comprising 30 families.

Methods

Thirty index cases and seven affected family members were included and categorized as follows: (i) 24 families with 28 patients initially diagnosed with MYO, and (ii) six families with nine patients clinically diagnosed with CMS. Based on pedigree analysis, seven of the 30 families demonstrated autosomal dominant (AD) inheritance, 20 showed autosomal recessive (AR) inheritance, and three appeared to be sporadic. Informed consent was obtained from all participants. The investigative approach combined Whole-Exome Sequencing (WES) with WES-based copy number variation (CNV) analysis. Variants were prioritized according to ACMG classification criteria, along with in silico prediction tools including MutationTaster, SIFT, CADD, DANN, and REVEL. Segregation analysis of candidate variants was performed using PCR-based Sanger sequencing. All genetic analyses were conducted in accordance with standard laboratory protocols.

Results

Using this approach, 23 of the 30 index cases were genetically resolved. Among these, 17 patients exhibited AR inheritance and six showed AD inheritance. A total of 27 distinct variants in 16 genes were identified, including eight novel and 19 previously reported variants, all of which are associated with disease phenotypes in OMIM. Among MYO patients, variants in ANO5, PYGM, CLCN1, and DYSF were each identified in two families, while variants in other genes were observed in single families. In CMS patients, variants in the CHRNE gene were the most frequently detected. The identified variants showed consistency with known genotype–phenotype relationships.

Conclusions

Differential diagnosis in neuromuscular disorders can be particularly challenging due to overlapping phenotypes. Following clinical evaluation, genetic analysis plays a crucial role in establishing an accurate diagnosis. In this Turkish cohort, characterized by high consanguinity and notable ethnic diversity, WES analysis identified eight novel variants, thereby expanding the mutational spectrum of MYO and CMS and contributing to genotype–phenotype correlations. The four unresolved cases may be partially explained by the limitations of WES, including reduced sensitivity for detecting structural variants and alterations in non-coding regions. Additionally, some cases may involve non-Mendelian or more complex inheritance patterns. Overall, these findings enhance our understanding of the clinical and genetic landscape of MYO and CMS in the Turkish population. Given that future therapeutic strategies will increasingly rely on genetic insights, comprehensive molecular analyses will be essential for improving patient management and advancing personalized medicine.

References

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