Monograph: Guidelines for Genetic Testing of Peripheral Nerve Disorders-Article

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This AANEM monograph provides practical guidelines for genetic testing in inherited peripheral neuropathies (IPNs), a common and highly heterogeneous group of disorders affecting about 1 in 2500 people. It emphasizes that diagnosis should begin with careful clinical phenotyping, neurophysiology, and family history, because symptoms such as distal weakness, sensory loss, foot deformities, reduced reflexes, and specific conduction patterns can strongly suggest particular genetic subtypes.<br /><br />The article reviews how testing strategies have evolved from sequential single-gene testing to next-generation sequencing (NGS). In the United States, multigene NGS panels are generally the most cost-effective first-line approach for most suspected cases, while targeted tests remain appropriate when a specific diagnosis is strongly suspected, such as PMP22 duplication in classic CMT1A or PMP22 deletion in HNPP. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are recommended for atypical, syndromic, or panel-negative cases, with WGS offering the broadest detection of sequence variants, copy number changes, and noncoding alterations. The paper highlights important technical pitfalls, including variable panel content, difficult regions such as SORD, and missed repeat expansions such as RFC1 in CANVAS.<br /><br />A major section addresses best practices in variant interpretation using ACMG/AMP standards, with attention to population frequency, computational predictions, functional data, segregation, and phenotype matching. Variants of uncertain significance (VUS) require cautious counseling and periodic reanalysis.<br /><br />The monograph also explains why a precise genetic diagnosis matters: it improves prognosis, guides management, prevents unnecessary testing, supports cascade testing and reproductive counseling, identifies treatable conditions such as transthyretin amyloidosis, and opens access to clinical trials and emerging gene-based therapies. Genetic counseling before and after testing is stressed as essential, as are ethical considerations in children and asymptomatic adults.

Keywords

inherited peripheral neuropathies

genetic testing

next-generation sequencing

multigene panel

whole-exome sequencing

whole-genome sequencing

PMP22 duplication

variant interpretation

genetic counseling

ACMG AMP standards