High diagnostic yield with algorithmic molecular approach on hereditary neuropathies.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Charcot-Marie-Tooth disease (CMT) encompasses a spectrum of inherited peripheral neuropathies.
• Accurate molecular diagnosis is crucial for understanding CMT subtypes and prognosis.

Purpose of the Study:

• To evaluate the efficacy of targeted next-generation sequencing (NGS) panels in the clinical diagnosis of Charcot-Marie-Tooth disease.
• To assess the limitations and diagnostic yield of NGS and whole-exome sequencing (WES) in CMT.
• To explore the role of genetic analysis in routine CMT diagnostics.

Main Methods:

• Retrospective analysis of 64 patients with suspected Charcot-Marie-Tooth disease.
• Utilized multiplex ligation probe amplification (MLPA), targeted NGS panels, and whole-exome sequencing (WES).
• Compared diagnostic yields across different molecular genetic testing methods.

Main Results:

• Multiplex ligation probe amplification (MLPA) diagnosed 39% of patients.
• Targeted NGS panels identified pathogenic/likely pathogenic variants in 36% of analyzed CMT patients.
• Whole-exome sequencing (WES) achieved an 80% diagnostic yield in cases with initially normal NGS results, particularly in pediatric patients.

Conclusions:

• A combined approach using pre-test evaluation, pedigree analysis, and clinical phenotype guides genetic testing algorithms for CMT.
• NGS and WES are valuable tools for molecular diagnosis of Charcot-Marie-Tooth disease, but limitations persist.
• Undiagnosed cases highlight the need for further research into novel genes and mechanisms underlying CMT.