We used a targeted panel to evaluate 119 patients who had an unexplained axonal neuropathy, with or without a family history, and for whom prior genetic testing had not provided a diagnosis.

Charcot-Marie-Tooth disease (CMT) affects 1 in 2,500 people. Mutations in PMP22, GJB1, MPZ, and MFN2 are the most common causes, but mutations in more than 100 different genes also cause CMT.

All patients had an outpatient evaluation, and clinical neurophysiology that included the left arm.  The age of clinical onset ranged from early childhood to 73 years (mean = 41 years; mode = 50 years). The gene panel contained 72 (n=81), 83 (n=37), or 105 (n=1) neuropathy-associated genes. For each case, we reviewed the interpretation of the clinical laboratory, and used gnomAD to evaluate all variants of unknown significance (VUS).

Of patients with a family history of neuropathy (N=73), the panel identified pathogenic variants in (1) TRPV4 (c.947G>A; p.Arg316His) in a  29-year-old man with early onset, motor > sensory axonal neuropathy, and (2) MFN2 (c.2230G>A; p.Glu744Lys) in a 44-year-old man with a clinical onset at age 20. Of the patients without a family history (N=52), the gene panel identified pathogenic variants in (1) SPTLC2 (c.547C>T; p.Arg183Trp) in a 63-year-old man with a clinical onset dating to age 20, and (2) a PMP22 deletion in a 69-year-old man with a late-onset axonal neuropathy with features of HNPP. The laboratory also reported 115 VUS in 78 patients (0, n=41; 1, n=50; 2, n=20; 3, n=7; 4, n=1), including a MFN2 mutation (c.2230G>A; p.Glu744Lys) that we believe to be pathogenic.

In summary, a large “neuropathy panel” does not provide a genetic answer for most patients who have an axonal neuropathy regardless of a family history of neuropathy.