Department of Genomics, Turku University Hospital, Turku, Finland.
Research Unit of Clinical Medicine and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
Mol Genet Genomic Med. 2024 Sep;12(9):e70014. doi: 10.1002/mgg3.70014.
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.
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.
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.
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.
X 连锁隐性 3 型腓骨肌萎缩症（CMTX3）是儿童发病型 CMT 的一种罕见亚型。迄今为止，所有报道的 CMTX3 患者均携带共同的 78kb 染色体 8 插入到 Xq27.1 回文区的遗传基础。
我们对一名患有临床诊断的 Dejerine-Sottas 病的男性患者进行了患者-父母三人体光学基因组图谱（OGM）分析，该患者的初始标准遗传诊断测试，包括全基因组测序（WGS），结果均为阴性。
OGM 分析显示，一条来自染色体 7q31.1 到 Xq27.1 的染色体间插入，呈母系遗传。结合对 WGS 数据的手动重新评估，这证实了非典型 CMTX3 的分子诊断，并表明插入的 122.4kb 片段包含 DLD 和部分 LAMB1。随后的分析证实，该重排是先证者母亲的新生突变。
我们报告了第二个与 CMTX3 相关的 Xq27.1 重排，为其表型和基因型谱提供了新的临床见解。我们的发现强调了在儿童发病型 CMT 的标准诊断流程中包括 Xq27.1 基因组重排分析的重要性。鉴于染色体 7 和 8 的插入导致的多发性神经病表型重叠，CMTX3 中周围神经病的发病机制可能涉及该区域内基因的失调。
