De novo somatic mosaicisms of INF2 and TRPV4 in patients with Charcot-Marie-Tooth disease.

Abstract

Background: Somatic mosaicism is caused by a postzygotic de novo mutation. It is a very rare genetic event, and mosaic cases have been reported only very limitedly among Korean patients with peripheral neuropathies, including Charcot-Marie-Tooth disease (CMT) so far.

Objective: This study was performed to identify and characterize somatic mosaicism in Korean families with CMT.

Methods: Genetic causes were identified by whole exome sequencing (WES) and a subsequent filtering process of the variants. The level of mosaicism for the de novo somatic mutations was determined by counting altered sequences from approximately 100 colonies/mutation and the ratio of altered sequences per total reads at the mutation site using the WES data.

Results: We observed two cases of somatic mosaicism in different families with CMT: p.Cys104Tyr in INF2 (male with CMT1) and p.Ser729Arg in TRPV4 (female with CMT2). The approximate levels of mosaicism were determined to be 24% and 30% in the blood, respectively. A man with the INF2 mutation showed very mild symptoms, while a woman with the TRPV4 mutation showed severe clinical phenotypes. The INF2 mutation is specifically considered a case of gonadal mosaicism. In addition, we confirmed that the p.Cys104Tyr in INF2 is associated with the CMT1 phenotype without focal segmental glomerulosclerosis (FSGS).

Conclusion: This study may be the first or second report for the INF2 and TRPV4 mosaicism. The degrees of the phenotypic severity for the mosaic mutations probably depend on the mutation sites and the levels of mosaicism in the affected tissues. This study suggests that somatic mosaicism may contribute to inter- or intra-familial phenotypic heterogeneity.