Novel mutations in the sacsin gene in ataxia patients from Maritime Canada
Novel mutations in the sacsin gene in ataxia patients from Maritime Canada
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DOI：
10.1016/j.jns.2009.09.034
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发表时间：
2010-01-15
影响因子：
4.4
通讯作者：
Samuels, M. E.
中科院分区：
文献类型：
--
作者：
Guernsey, D. L.;Dube, M. -P.;Samuels, M. E.
我们在加拿大东部确定了两个家庭，分离出一种形式的共济失调，符合隐性遗传模式。我们使用密集SNP基因分型进行了全基因组扫描，尽管在我们定义的13号染色体上的一个小区域缺乏共同的纯合性，但我们定义了与13号染色体上的一个小区域相关联的基因。直接DNA重测序用于筛选这一区间内与生物相关的候选基因，并在编码sacsin的基因中发现了两个假定的致病突变。一个变种是专性截断突变，第二个是高度保守残基中的错义变种。出乎意料的是，一个家庭是错义突变的纯合子，另一个家庭是两个突变的杂合子。我们的结果扩大了Sacsin基因突变的基因型表型相关性，并突出了主要基于临床原因诊断遗传异质性疾病的挑战。我们证明，适度规模的全基因组基因分型可以在研究中产生成效，并有可能在临床上应用。(C)2009爱思唯尔B.V.保留所有权利。
We ascertained two families in Eastern Canada segregating a form of ataxia consistent with a recessive mode of inheritance. We performed a whole genome scan using dense SNP genotyping, and despite an absence of shared homozygosity in the families we defined linkage to a small region on chromosome 13. Direct DNA resequencing was employed to screen biologically relevant candidate genes in the interval, and two presumptive pathogenic mutations were found in the gene encoding sacsin. One variant is an obligate truncating mutation, the second is a missense variant in a highly conserved residue. Unexpectedly, one family was homozygous for the missense mutation, the other compound heterozygous for the two mutations. Our results expand the genotype phenotype correlation of mutations in the sacsin gene, and highlight the challenge of diagnosing genetically heterogeneous disorders on primarily clinical grounds. We demonstrate that whole genome genotyping on a modest scale can be productive in research, and potentially in a clinical context. (C) 2009 Elsevier B.V. All rights reserved.