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.