Diagnostic yield of clinical exome sequencing in patients with suspected hereditary neuropathy

Hereditary neuropathies exhibit significant genetic heterogeneities, often making molecular diagnosis challenging. Clinical Exome Sequencing (CES) allows the simultaneous evaluation of a wide range of candidate genes, and can be considered an efficient approach to identifying underlying genetic causes. The present study assesses the diagnostic utility of CES in patients with clinically suspected hereditary neuropathy.

Included in the study were 21 patients with clinically suspected hereditary neuropathy who underwent CES. DNA samples were isolated from peripheral blood and subjected to CES on an Illumina NextSeq 2000 system, while a bioinformatics analysis and variant interpretation were performed using Sophia DDM® software. All identified variants were classified according to the most recent American College of Medical Genetics and Genomics (ACMG) guidelines.

Pathogenic or likely pathogenic variants were identified in seven patients (33.3%), of whom six (28.5%) had a confirmed molecular diagnosis consistent with the clinical phenotype. Variants of uncertain significance (VUS) were detected in nine patients (42.8%), while no clinically relevant variants were found in five (23.8%).

CES contributed significantly to the establishment of molecular diagnoses in nearly one-third of the studied cohort. However, the high prevalence of VUS underscores the limitations of current interpretation frameworks, revealing a need for functional validation and familial segregation analyses. Despite these challenges, CES remains a valuable and appropriate diagnostic tool, particularly in resource-limited healthcare settings.