Homozygosity mapping and next generation sequencing for the genetic diagnosis of hereditary ataxia and spastic paraplegia in consanguineous families
Homozygosity mapping and next generation sequencing for the genetic diagnosis of hereditary ataxia and spastic paraplegia in consanguineous families
复制标题
近亲遗传性共济失调和痉挛性截瘫基因诊断的纯合性作图和二代测序
DOI：
10.1016/j.parkreldis.2020.09.013
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发表时间：
2020-11-01
影响因子：
4.1
通讯作者：
Shen, Lu
中科院分区：
文献类型：
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作者：
Jiao, Bin;Zhou, Zhifan;Shen, Lu
前言：遗传在有血缘关系的共济失调和/或痉挛截瘫患者中起着关键作用。本研究旨在阐明常染色体隐性遗传性共济失调和痉挛性截瘫(AR-HA/HSPs)患者的遗传谱。方法：收集中国地区36个AR-HA/HSPs血缘家系。结果：在AR-HA/HSPs家系中，47.2%(17/36)的家系进行了分子诊断。其中13株AR-HAS携带SETX(n=4)、SACS(n=2)、STUB1、HSD17B4、NEU1、ADCK3、TPP1、PLA2G6和MTCL1致病变异，4株AR-HSP携带SPG11、ZFYVE26、ATP13A2和ABCD1致病变异。在一个AR-HA家系中发现1个MRPS27纯合子无义突变，该突变可能是AR-HA的一个新的候选基因。结论：Hm和NGS可作为AR-HA/HSPs的有效分子诊断工具。我们的发现为更好地了解AR-HA/HSPs的血缘遗传结构提供了更好的理解，并拓宽了该疾病的临床遗传谱。
Introduction: Genetic inheritance plays key roles in patients with ataxia and/or spastic paraplegia in consanguineous families. This study aims to clarify the genetic spectrum of patients with autosomal recessive hereditary ataxia and spastic paraplegias (AR-HA/HSPs) in consanguineous families.Methods: A total of 36 AR-HA/HSPs consanguineous pedigrees from China were recruited into this study. Next generation sequencing (NGS), guided by homozygosity mapping (HM), was applied to identify the pathogenic variants in known genes or novel candidate genes.Results: We totally made molecular diagnosis in 47.2% (17/36) of AR-HA/HSPs families. Among them, 13 AR-HAs carried pathogenic variants in SETX (n = 4), SACS (n = 2), STUB1, HSD17B4, NEU1, ADCK3, TPP1, PLA2G6 and MTCL1, while four AR-HSPs carried pathogenic variants in SPG11, ZFYVE26, ATP13A2 and ABCD1. One homozygous nonsense mutation in MRPS27 was identified in an AR-HA family, which was potentially a novel candidate gene of AR-HA.Conclusion: HM and NGS can serve as an efficient molecular diagnostic tool for AR-HA/HSPs in consanguineous families. Our findings provide a better understanding of genetic architecture of AR-HA/HSPs in consanguinity and broaden the clinical-genetic spectrum of the disease.