McGlasson Sarah, Rannikmäe Kristiina, Bevan Steven, Logan Clare, Bicknell Louise S, Jury Alexa, Jackson Andrew P, Markus Hugh S, Sudlow Cathie, Hunt David P J
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
Wellcome Open Res. 2017 Nov 2;2:106. doi: 10.12688/wellcomeopenres.12631.1. eCollection 2017.
Monoallelic and biallelic mutations in the exonuclease cause monogenic small vessel diseases (SVD). Given recent evidence for genetic and pathophysiological overlap between monogenic and polygenic forms of SVD, evaluation of in small vessel stroke is warranted. We sequenced the gene in an exploratory cohort of patients with lacunar stroke (Edinburgh Stroke Study, n=290 lacunar stroke cases). We subsequently performed a fully blinded case-control study of early onset MRI-confirmed small vessel stroke within the UK Young Lacunar Stroke Resource (990 cases, 939 controls). No patients with canonical disease-causing mutations of were identified in cases or controls. Analysis of an exploratory cohort identified a potential association between rare variants of and patients with lacunar stroke. However, subsequent controlled and blinded evaluation of in a larger and MRI-confirmed patient cohort, the UK Young Lacunar Stroke Resource, identified heterozygous rare variants in 2.1% of cases and 2.3% of controls. No association was observed with stroke risk (odds ratio = 0.90; 95% confidence interval, 0.49-1.65 p=0.74). Similarly no association was seen with rare variants with predicted deleterious effects on enzyme function (odds ratio = 1.05; 95% confidence interval, 0.43-2.61 p=0.91). No patients with early-onset lacunar stroke had genetic evidence of a -associated monogenic microangiopathy. These results show no evidence of association between rare variants of and early onset lacunar stroke. This includes rare variants that significantly affect protein and enzyme function. Routine sequencing of the gene in patients with early onset lacunar stroke is therefore unlikely to be of diagnostic utility, in the absence of syndromic features or family history.
核酸外切酶中的单等位基因和双等位基因突变会导致单基因性小血管疾病（SVD）。鉴于最近有证据表明单基因和多基因形式的SVD在遗传和病理生理方面存在重叠，因此有必要对小血管性卒中中的[该基因名称未给出]进行评估。我们对一组腔隙性卒中患者（爱丁堡卒中研究，n = 290例腔隙性卒中病例）进行了探索性队列研究，对[该基因名称未给出]进行了测序。随后，我们在英国青年腔隙性卒中资源库中进行了一项完全盲法的病例对照研究，研究对象为早期发病且经MRI证实的小血管性卒中（990例病例，939例对照）。在病例组或对照组中均未发现具有[该基因名称未给出]典型致病突变的患者。对探索性队列的分析发现[该基因名称未给出]的罕见变异与腔隙性卒中患者之间存在潜在关联。然而，随后在一个更大的且经MRI证实的患者队列——英国青年腔隙性卒中资源库中对[该基因名称未给出]进行的对照和盲法评估发现，2.1%的病例和2.3%的对照中存在杂合罕见变异。未观察到与卒中风险的关联（优势比 = 0.90；95%置信区间，0.49 - 1.65；p = 0.74）。同样，对于预测对酶功能有有害影响的罕见[该基因名称未给出]变异也未发现关联（优势比 = 1.05；95%置信区间，0.43 - 2.61；p = 0.91）。没有早期发病的腔隙性卒中患者有与[该基因名称未给出]相关的单基因微血管病的遗传证据。这些结果表明，没有证据表明[该基因名称未给出]的罕见变异与早期发病的腔隙性卒中之间存在关联。这包括显著影响蛋白质和酶功能的罕见变异。因此，在没有综合征特征或家族史的情况下，对早期发病的腔隙性卒中患者进行[该基因名称未给出]基因的常规测序不太可能具有诊断价值。
