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Abstract Details

Benefits of a Small Gene Panel for CMT in the Era of Genomics
Neuromuscular and Clinical Neurophysiology (EMG)
S42 - Neuromuscular Disorders (4:36 PM-4:47 PM)
007

CMT and related hereditary forms of peripheral neuropathies (PNs) represent a genetically heterogeneous group of disorders with an estimated prevalence of 1 in 2500. However, there are a few genes (PMP22, GJB1, MPZ, and MFN2) with relatively high diagnostic yields, particularly for CMT type 1. As genetic testing moves toward large panels and exome/genome sequencing, the utility of small, targeted panels may be undervalued.

To assess the utility of a four gene panel for molecular diagnosis of Charcot-Marie-Tooth (CMT) neuropathy.

Genetic testing for inherited peripheral neuropathy was performed on 1216 individuals referred to our diagnostic laboratory using next generation sequencing and exon-level array CGH for one of two panels: a “core” CMT panel (PMP22, GJB1, MPZ, and MFN2) and a larger hereditary neuropathy panel (36 CMT genes including the four core CMT genes and up to 18 other neuropathy-associated genes).
The neuropathy panel yielded a positive diagnostic rate (PDR) of 20.3% (231/1136) while the core panel PDR was 26.3% (21/80). Pathogenic or likely pathogenic variants in core panel genes made up the bulk of positive findings for the larger neuropathy panel and accounted for 70.6% of all positive cases. About half of those positive findings (53%) were identified in the PMP22 gene. Moreover, the core panel had a low VUS rate of ~4% (3/80) compared to ~49% (558/1136) for the neuropathy panel (p<0.0001).

Our data demonstrate that genetic testing for CMT via a thoughtfully designed, small genetic testing panel with well-established genes can be an advantageous option for physicians interested in a test with a high diagnostic yield and low VUS rate. This will reduce the burden for practices with limited genetic counselor resources. If desired, a tiered testing approach with reflex to a larger multi-gene panel or exome sequencing could be considered.

Authors/Disclosures
Houda Elloumi, PhD (Genedx)
PRESENTER
No disclosure on file
No disclosure on file
Dianalee McKnight, PhD (InVitae) Dr. McKnight has nothing to disclose.
Tracy Brandt, PhD (GeneDx, Inc.) No disclosure on file