From the Department of Clinical Sciences Lund, Neurology (A.I., A.P., A.L.), Lund University, Sweden.
Department of Neurology and Rehabilitation Medicine, Neurology, Skåne University Hospital, Sweden (A.L., A.P., A.L.).
Stroke. 2020 Apr;51(4):1056-1063. doi: 10.1161/STROKEAHA.119.027474. Epub 2020 Mar 16.
Backgrounds and Purpose- Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke. Methods- We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands' clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes. Results- Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in and a possibly pathogenic variant in gene were identified. A novel :c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete. c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke, c.148C>G (p.Leu50Val), and :c.2416A>G (p.Ile806Val); c.808A>G (p.Ile270Val), c.1294dupG (p.Val432fs), : c.1070C>T (p.Ala357Val), and c.392G>A (p.Arg131His), respectively. Conclusions- Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.
背景与目的- 尽管新的遗传分析方法正在迅速发展，但目前在如何检测孟德尔形式的中风方面仍存在知识空白。方法- 我们对 22 名首次缺血性中风发作年龄在 56 岁以下的多事件中风家族的先证者进行了全外显子组测序。使用全面的中风基因谱，我们在与这些基因相关的中风相关基因中寻找变体。先证者的临床中风亚型与先前与这些基因的致病性变体相关的临床特征有关。在 7 个家族中对亲属进行基因分型，以评估中风基因的未知意义变体。在 2 个具有不明来源栓塞性中风的较大家族中，对额外的成员进行全外显子组测序，以检查鉴定新的中风基因的可能性。结果- 22 名先证者中有 6 名携带先前与中风亚型相关的基因中的致病性或可能致病性变体。在 基因中发现了一个已知的致病性变体和 基因中的一个可能的致病性变体。在一名具有不明来源栓塞性中风和血栓前状态的先证者中发现了一个新的 ：c.3188G>A（p.Arg1063His）突变。然而，家族中的外显率不完全。在 2 名先证者中检测到 c.3368A>G（p.Glu1123Gly），但在他们的家族中未与疾病共分离。对 2 个具有不明来源栓塞性中风的家系中多个成员进行全外显子组测序，发现了先前与中风无关的基因中的可能致病性变体 c.148C>G（p.Leu50Val）和 ：c.2416A>G（p.Ile806Val）； c.808A>G（p.Ile270Val）、c.1294dupG（p.Val432fs）、 ：c.1070C>T（p.Ala357Val）和 c.392G>A（p.Arg131His），分别。结论- 使用全面的中风基因谱进行全外显子组测序筛查可能会发现罕见的单基因形式的中风，但仔细评估临床特征和新变体的潜在致病性仍然很重要。在我们的研究中，大多数具有中风家族聚集的个体都没有发现任何确定的遗传原因。
