Diagnostic yield of advanced genetic testing in patients with hereditary neuropathies: A retrospective single‐site study

Introduction/Aims Advanced genetic testing including next‐generation sequencing (AGT/NGS) has facilitated DNA testing in the clinical setting and greatly expanded new gene discovery for the Charcot‐Marie‐Tooth neuropathies and other hereditary neuropathies (CMT/HN). Herein, we report AGT/NGS results, clinical findings, and diagnostic yield in a cohort of CMT/HN patients evaluated at our neuropathy care center. Methods We reviewed the medical records of all patients with suspected CMT/HN who underwent AGT/NGS at the Hospital for Special Care from January 2017 through January 2020. Patients with variants reported as pathogenic or likely pathogenic were included for further clinical review. Results We ordered AGT/NGS on 108 patients with suspected CMT/HN. Of these, pathogenic or likely pathogenic variants were identified in 17 patients (diagnostic yield, 15.7%), including 6 (35%) with PMP22 duplications; 3 (18%) with MPZ variants; 2 (12%) with MFN2 variants; and 1 each with NEFL, IGHMBP2, GJB1, BSCL2, DNM2, and TTR variants. Diagnostic yield increased to 31.0% for patients with a positive family history. Discussion AGT/NGS panels can provide specific genetic diagnoses for a subset of patients with CMT/HN disorders, which improves disease and genetic counseling and prepares patients for disease‐focused therapies. Despite these advancements, many patients with known or suspected CMT/HN disorders remain without a specific genetic diagnosis. Continued advancements in genetic testing, such as multiomic technology and better understanding of genotype‐phenotype correlation, will further improve detection rates for patients with suspected CMT/HN disorders.