WASHINGTON, DC—Inherited neuropathies such as Charcot-Marie-Tooth disease (CMT) can be diagnosed effectively through multigene panels, according to results presented at the 67th Annual Meeting of the American Academy of Neurology. The findings indicate that the phenotypic spectrum of these disorders may be broader than the literature has reported.
Study Included 252 Patients
Courtney Downtain Pickersgill, Senior Genetic Counselor at GeneDx in Gaithersburg, Maryland, and colleagues performed clinical molecular testing on 252 patients using a multigene panel testing approach. These tests used next-generation sequencing and exon-level copy number analysis to evaluate 50 genes associated with inherited neuropathy. Reported variants were confirmed using an appropriate method.
Courtney Downtain Pickersgill
Neuropathies can be subdivided into several categories, including hereditary motor and sensory neuropathies, hereditary motor neuropathies, and hereditary sensory and autonomic neuropathies. Because of the considerable phenotypic and genetic overlap among these disorders, inherited neuropathies are well suited for multigene panel testing, the authors noted.
Expected and Unexpected Results
In 22% of cases, the tests yielded a positive diagnostic result for inherited neuropathy. Positive results were defined as a pathogenic or likely pathogenic variant in an autosomal dominant or X-linked disorder, or two pathogenic variants or one pathogenic variant and one likely pathogenic variant in an autosomal recessive disorder. A test was not considered positive if only one pathogenic variant associated with recessive inheritance was detected.
The most common finding, representing 27% of positive cases, was the whole-gene duplication of peripheral myelin protein 22 (PMP22), which is implicated in CMT type 1A. The PMP22 duplication rate may appear to be lower than expected, the researchers acknowledged. Several considerations may explain the seeming discrepancy, however. First, some physicians may have used the test to evaluate patients with CMT who already had been confirmed negative for the common etiologies, such as PMP22 duplication. Second, because the gene panel was designed to evaluate CMT and related neuropathies, some of the patients for whom the panel was ordered did not have CMT. Thus the subjects did not constitute a CMT cohort.
Other findings included gene mutations in gap junction protein, beta-1 (GJB1, 16%); mitofusin-2 (MFN2, 13%); and myelin protein zero (MPZ, 7%). The results were consistent with the relatively high frequency of mutations in these particular genes in persons with neuropathies. Nevertheless, “several positive cases had reported clinical features outside the known spectrum for the disorder,” the authors said. Unexpected nerve conduction velocity results, unusual age of onset, and uncommon muscular symptoms were among the atypical clinical features. Furthermore, 32% of positive cases had genetic mutations that are less commonly found in CMT and related disorders, including GARS, GLA, and TTR. Therefore, if a “wide net” had not been cast, these anomalous cases would have been difficult to diagnose, the investigators suggested.
—Adriene Marshall