Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy.
Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy.
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DOI：
10.1056/nejmoa0908094
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发表时间：
2010-04-01
期刊：
影响因子：
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通讯作者：
Gibbs RA
中科院分区：
文献类型：
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作者：
Lupski JR;Reid JG;Gonzaga-Jauregui C;Rio Deiros D;Chen DC;Nazareth L;Bainbridge M;Dinh H;Jing C;Wheeler DA;McGuire AL;Zhang F;Stankiewicz P;Halperin JJ;Yang C;Gehman C;Guo D;Irikat RK;Tom W;Fantin NJ;Muzny DM;Gibbs RA
通过快速识别致病等位基因，全基因组测序可能会给医学诊断带来革命性的变化。然而，即使在遗传模式简单且诊断明确的病例中，疾病表型与其相应的遗传变化之间的关系也可能是复杂的。因此，全面的诊断分析必须确定每个单倍型中所有可能的DNA变化，并确定哪些是导致潜在疾病的原因。在所有人类中存在大量罕见的异质突变，并且在90%以上的注释基因中缺乏已知的功能变体，这使得这一挑战尤其困难。因此，通过全基因组测序来鉴定遗传疾病的分子基础仍然是难以捉摸的。因此，我们的目的是评估人类全基因组测序对腓骨肌萎缩症患者遗传诊断的有用性。我们确定了一个家族与隐性形式的腓骨肌萎缩症，其遗传基础尚未确定。我们对先证者的全基因组进行了测序，确定了所有可能与该疾病相关的基因的潜在功能变异，并在受影响的家庭成员中对这些变异进行了基因分型。我们鉴定并验证了SH3TC2 （SH3结构域和四肽重复2基因）的复合杂合致病等位基因，涉及两个突变，在先证者和患有沙克-玛丽- tooth病的家庭成员中。单独的亚临床表型与两个突变中的每一个独立分离；杂合突变使神经病变易感性，包括腕管综合征。本研究对一个患有腓骨肌萎缩症的家庭进行了研究，结果表明，全基因组测序可以识别临床相关的变异，并提供诊断信息，为患者的护理提供信息。
Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot–Marie–Tooth disease. We identified a family with a recessive form of Charcot–Marie–Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members. We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome. As shown in this study of a family with Charcot–Marie–Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.