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

IF 1.5 4区 医学 Q4 GENETICS & HEREDITY
Elisa Rahikkala, Jonna Komulainen-Ebrahim, Jussi-Pekka Tolonen, Sandra Vorimo, Maria Suo-Palosaari, Päivi Vieira, Johanna Piispala, Johanna Uusimaa, Katri Pylkäs, Tuomo Mantere
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引用次数: 0

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.

光学基因组图谱发现与夏科-玛丽齿神经病 CMTX3 有关的第二个 Xq27.1 重排。
背景:X 连锁隐性 3 型夏科-玛丽-牙病(CMTX3)是儿童发病型夏科-玛丽-牙病的一种罕见亚型。迄今为止,所有报道的 CMTX3 患者都有一个共同的创始基因,即从 8 号染色体插入到 Xq27.1 palindrome 区域的 78 kb:我们对一名临床诊断为 Dejerine-Sottas 病的男性患者进行了患者-父母三人光学基因组图谱(OGM)分析,包括全基因组测序(WGS)在内的初步标准基因诊断测试结果均为阴性:结果:OGM 分析显示,从染色体 7q31.1 区到 Xq27.1 区存在母系遗传的染色体间插入。结果:OGM 分析显示,染色体间插入物从染色体 7q31.1 区进入 Xq27.1,再加上手动重新评估 WGS 数据,证实了非典型 CMTX3 的分子诊断,并显示 122.4 kb 插入片段包含 DLD 和部分 LAMB1。 随后的分析证实,该重排是在患者母亲体内从头产生的:我们报告了第二例与 CMTX3 相关的 Xq27.1 基因重排,为临床了解其表型和基因型谱提供了新的视角。我们的研究结果凸显了将 Xq27.1 基因组重排分析纳入儿童发病型 CMT 标准诊断流程的重要性。鉴于 7 号和 8 号染色体插入同一 Xq27.1 宫位区所导致的多发性神经病表型的重叠,CMTX3 周围神经病变的致病机制可能涉及该区域内基因的失调。
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来源期刊
Molecular Genetics & Genomic Medicine
Molecular Genetics & Genomic Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
4.20
自引率
0.00%
发文量
241
审稿时长
14 weeks
期刊介绍: Molecular Genetics & Genomic Medicine is a peer-reviewed journal for rapid dissemination of quality research related to the dynamically developing areas of human, molecular and medical genetics. The journal publishes original research articles covering findings in phenotypic, molecular, biological, and genomic aspects of genomic variation, inherited disorders and birth defects. The broad publishing spectrum of Molecular Genetics & Genomic Medicine includes rare and common disorders from diagnosis to treatment. Examples of appropriate articles include reports of novel disease genes, functional studies of genetic variants, in-depth genotype-phenotype studies, genomic analysis of inherited disorders, molecular diagnostic methods, medical bioinformatics, ethical, legal, and social implications (ELSI), and approaches to clinical diagnosis. Molecular Genetics & Genomic Medicine provides a scientific home for next generation sequencing studies of rare and common disorders, which will make research in this fascinating area easily and rapidly accessible to the scientific community. This will serve as the basis for translating next generation sequencing studies into individualized diagnostics and therapeutics, for day-to-day medical care. Molecular Genetics & Genomic Medicine publishes original research articles, reviews, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented.
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