Optical Genome Mapping Identifies a Second Xq27.1 Rearrangement Associated With Charcot–Marie–Tooth Neuropathy CMTX3

ABSTRACT Background X‐linked recessive type 3 Charcot–Marie–Tooth (CMTX3) is a rare subtype of childhood‐onset CMT. To date, all reported CMTX3 patients share a common founder 78 kb insertion from chromosome 8 into the Xq27.1 palindrome region. Methods We conducted patient–parent trio optical genome mapping (OGM) on a male patient presenting with clinically diagnosed Dejerine–Sottas disease for whom initial standard diagnostic genetic tests, including whole‐genome sequencing (WGS), yielded negative results. Results OGM analysis revealed a maternally inherited interchromosomal insertion from chromosome region 7q31.1 into Xq27.1. Coupled with manual reassessment of WGS data, this confirmed the molecular diagnosis of atypical CMTX3 and showed that the 122.4 kb inserted fragment contained DLD and partially LAMB1. Subsequent analyses confirmed that the rearrangement had arisen de novo in the proband's mother. Conclusion We report the second Xq27.1 rearrangement associated with CMTX3, providing novel clinical insights into its phenotypic and genotypic spectrum. Our findings highlight the importance of including genomic rearrangement analysis of Xq27.1 in standard diagnostic pipelines for childhood‐onset CMT. Given the overlap in polyneuropathy phenotypes resulting from insertions from chromosomes 7 and 8 into the same Xq27.1 palindrome region, the pathogenic mechanism underlying peripheral neuropathy in CMTX3 likely involves dysregulation of genes within this region.