Next-generation sequencing approach to hyperCKemia: A 2-year cohort study

Area of Science:

• Clinical Neurology
• Molecular Genetics
• Genomic Medicine

Background:

• HyperCKemia (elevated creatine kinase levels) can indicate underlying muscular disorders.
• Many cases of asymptomatic or paucisymptomatic hyperCKemia remain molecularly undiagnosed.
• Genetic heterogeneity complicates the diagnosis of muscular dystrophies and myopathies.

Purpose of the Study:

• To evaluate the utility of next-generation sequencing (NGS) in diagnosing genetically undiagnosed hyperCKemia.
• To investigate the genetic basis of asymptomatic or paucisymptomatic hyperCKemia.
• To assess the diagnostic yield of targeted gene panels in neuromuscular disorders.

Main Methods:

• Analyzed 66 patients with undiagnosed hyperCKemia using a targeted NGS panel.
• The panel covered 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and myopathies.
• Investigated coding exons and flanking intronic regions for pathogenic variants.

Main Results:

• Achieved a 50% diagnostic yield, identifying the genetic cause in 33 out of 66 patients.
• Found variants of unknown significance in 26% of cases and remained undiagnosed in 24%.
• Common clinical features included mild proximal muscle weakness (27%) and myalgia (24%); 14 patients remained asymptomatic.

Conclusions:

• NGS is an effective first-tier diagnostic approach for genetically heterogeneous conditions like hyperCKemia.
• Isolated hyperCKemia can be an early sign of progressive muscular disorders.
• Molecular diagnosis advances clinical neurology by identifying genetic underpinnings and guiding surveillance.