GNB4 was first reported in relation to autosomal dominant Charcot-Marie-Tooth Disease in 2013 (Soong et al., PMID: 23434417). Reported cases to date have an adolescent onset and are further characterized by slowly progressive distal muscle atrophy and weakness, distal sensory impairment with decreased reflexes, and variable nerve conduction velocities ranging from the demyelinating to the axonal range. Four missense variants, two of which are de novo, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least four probands in three separate publications (PMIDs: 23134117, 28642160, 27908631). Variants in this gene segregated with disease in five additional family members in one large family. Although the initial characterization evidence to support pathogenicity, there is a lack of appropriate supporting evidence for the latter two cases. This gene-disease relationship is additionally supported by expression data and functional alteration of human oligodendrocyte progenitor cells (hOPCs). Investigation determined that GNB4 is largely expressed in axons and Schwann cells of neurons, relating to the neurodegenerative phenotypes characteristic of CMT. Additionally, mice with an immunodeficient, demyelinating phenotype were injected with hOPCs both expressing and not expressing GNB4 and found a large increase in the latter's differentiation compared to the controls, suggesting a major role in myelin development and differentiation. Although there is additional evidence available, the lack of the exact mechanism and an animal model limits the scorable data. In summary, there is MODERATE evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Charcot-Marie-Tooth Expert Panel on 02/25/20 (SOP Version 007).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.