Novel GNB4 Gene Variant and the Spectrum of GNB4 Variants in Patients With Charcot-Marie-Tooth Disease

Our aim was to report a novel variant of Guanine nucleotide-binding protein subunit beta-4 gene (GNB4) variants and to report the clinical and molecular spectrum of the GNB4-related neuropathy based on the currently reported cases.

We performed detailed neurologic and electrophysiologic assessments and segregation analysis in a patient form single family with Charcot-Marie-Tooth (CMT) disease with novel GNB4 variant. Via literature search, we found studies that included neuropathy cases with GNB4 variants; we then reviewed and reclassified these variants in accordance with the ACMG guidelines and latest databases and evidence.

We identified a novel GNB4 variant NM_021629.4:c.239T>C p.(Ile80Thr) in a single family with CMT. In total, we identified 8 GNB4 variants reported in the literature from 10 unrelated families in addition to the novel variant reported in this study. We compiled standardised clinical and genotypic information for 15 affected individuals from 8 families carrying 6 distinct likely pathogenic or pathogenic (LP/P) GNB4 variants reported in the literature and the variant found in this study. We found pathogenic variants to cluster on 3D in the GNB4 protein.

We reinterpreted the 8 previously reported GNB4 gene variants in the literature from 10 unrelated families in addition to the novel variant reported in this study in patients with hereditary neuropathy. We show that GNB4-associated neuropathy is associated with mixed axonal and demyelinating features presenting with usually symmetric lower limb motor weakness and sensory loss and/or upper limb weakness and sensory loss.