Diagnostic yield of a NGS panel in Brazilian patients with sporadic peripheral neuropathy

Abstract

Introduction: The etiology of sporadic peripheral neuropathy (PN) remains unclear in a significant proportion of patients. In European and North American surveys, genetic causes have been increasingly recognized in these patients. Little is known about Latin American populations. Objective: We assessed the diagnostic yield of a comprehensive next generation sequencing (NGS) panel in a cohort of Brazilian patients with PN without family history. Potential predictors of genetic etiology in this group were further explored. Methods: We evaluated 41 consecutive adult patients regularly followed with PN and 1. Negative family history of PN or other neurological disorders and 2. Unclear etiology despite extensive laboratorial/neurophysiological (Nerve Conduction Study+Electromyography [NCS+EMG]) workup. All patients then underwent genetic testing using a comprehensive (NGS) panel that included 72 genes known to cause PN. Only pathogenic or likely pathogenic variants according to American College of Medical Genetics and Genomics criteria were retrieved. For each subject, we recorded demographic, clinical and NCS+EMG data. Such variables were then compared between positive vs negative NGS subgroups using Fisher exact test (P < 0.05). Results: Fifteen patients had diagnostic NGS results (8 men, median age = 43 years old), whereas 26 patients (15 men, median age = 47 years old) had negative or unconclusive results. Diagnostic yield of the PN panel was 15/41 = 36.5%. Seventeen distinct variants were found in 5 different genes; PMP22 and SH3TC2 were the most frequently identified. Earlier age of PN onset (P = 0.013), demyelinating pattern on NCS+EMG (P = 0.021) and presence of distal atrophy on clinical examination (P= 0.043) were associated with positive NGS results. Conclusion: A significant proportion of Brazilian patients with sporadic PN has genetic etiology. NGS emerges as a diagnostically useful tool for idiopathic PN, particularly when there is earlier age at onset and demyelinating features.