Novel MORC2 variants in Charcot-Marie-Tooth disease type 2Z: genetic and functional insights.

BACKGROUND: Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an uncommon inherited condition characterized by autosomal dominant inheritance. It is marked by axonal neuropathy, leading to progressive muscle weakness, cramps, and sensory loss. MORC2 is one of the candidate pathogenic genes for CMT2Z. METHODS: Here, we enrolled two families affected by Charcot-Marie-Tooth (CMT) disease, with both families having probands who exhibit distal lower limb weakness. Whole-exome sequencing (WES) was used to explore the genetic lesion. RESULTS: Two heterozygous variants (NM_001303256, c.34G > C;p.A12P; NM_001303256, c.848G > A;p.R283H) of MORC2 gene were found. The c.848G > A;p.R283H variant is rare, and the c.34G > C;p.A12P variant has not been reported before. Functional studies revealed that the c.848G > A;p.R283H variant resulted in reduced transcription of the MORC2 gene. The c.34G > C;p.A12P variant did not impact MORC2 gene transcription, yet it influenced the protein's half-life and stability. Based on genetic analysis, two probands were subsequently diagnosed with CMT2Z. CONCLUSION: Our research contributed to the genetic assessment and guidance for these families, reinforcing the notion that MORC2 is a potential causative gene for CMT2Z.