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Abstract：
OBJECTIVE: Multiple factors play important roles in the occurrence and prognosis of stroke. However, the roles of monogenic variants in all-cause ischaemic stroke have not been systematically investigated. We aim to identify underdiagnosed monogenic stroke in an adult ischaemic stroke/transient ischaemic attack (TIA) cohort (the Third China National Stroke Registry, CNSR-III).
METHODS: Targeted next-generation sequencing for 181 genes associated with stroke was conducted on DNA samples from 10 428 patients recruited through CNSR-III. The genetic and clinical data from electronic health records (EHRs) were reviewed for completion of the diagnostic process. We assessed the percentages of individuals with pathogenic or likely pathogenic (P/LP) variants, and the diagnostic yield of pathogenic variants in known monogenic disease genes with associated phenotypes.
RESULTS: In total, 1953 individuals harboured at least one P/LP variant out of 10 428 patients. Then, 792 (7.6%) individuals (comprising 759 individuals harbouring one P/LP variant in one gene, 29 individuals harbouring two or more P/LP variants in different genes and 4 individuals with two P/LP variants in ABCC6) were predicted to be at risk for one or more monogenic diseases based on the inheritance pattern. Finally, 230 of 792 individuals manifested a clinical phenotype in the EHR data to support the diagnosis of stroke with a monogenic cause. The most diagnosed Mendelian cause of stroke in the cohort was cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There were no relationships between age or family history and the incidence of first symptomatic monogenic stroke in patients.
CONCLUSIONS: The rate of monogenic cause of stroke was 2.2% after reviewing the clinical phenotype. Possible reasons that Mendelian causes of stroke may be missed in adult patients who had an ischaemic stroke/TIA include a late onset of stroke symptoms, combination with common vascular risks and the absence of a prominent family history.
METHODS: Targeted next-generation sequencing for 181 genes associated with stroke was conducted on DNA samples from 10 428 patients recruited through CNSR-III. The genetic and clinical data from electronic health records (EHRs) were reviewed for completion of the diagnostic process. We assessed the percentages of individuals with pathogenic or likely pathogenic (P/LP) variants, and the diagnostic yield of pathogenic variants in known monogenic disease genes with associated phenotypes.
RESULTS: In total, 1953 individuals harboured at least one P/LP variant out of 10 428 patients. Then, 792 (7.6%) individuals (comprising 759 individuals harbouring one P/LP variant in one gene, 29 individuals harbouring two or more P/LP variants in different genes and 4 individuals with two P/LP variants in ABCC6) were predicted to be at risk for one or more monogenic diseases based on the inheritance pattern. Finally, 230 of 792 individuals manifested a clinical phenotype in the EHR data to support the diagnosis of stroke with a monogenic cause. The most diagnosed Mendelian cause of stroke in the cohort was cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There were no relationships between age or family history and the incidence of first symptomatic monogenic stroke in patients.
CONCLUSIONS: The rate of monogenic cause of stroke was 2.2% after reviewing the clinical phenotype. Possible reasons that Mendelian causes of stroke may be missed in adult patients who had an ischaemic stroke/TIA include a late onset of stroke symptoms, combination with common vascular risks and the absence of a prominent family history.
摘要：
目的：多因素在脑卒中的发生和预后中起重要作用。然而,单基因变异在全因缺血性卒中中的作用尚未得到系统研究.我们的目标是在成人缺血性卒中/短暂性脑缺血发作（TIA）队列中识别未确诊的单基因卒中（第三届中国国家卒中注册，CNSR-III)。
方法：对通过CNSR-III招募的10428名患者的DNA样本进行了181个与卒中相关基因的靶向下一代测序。审查了来自电子健康记录（EHR）的遗传和临床数据，以完成诊断过程。我们评估了具有致病性或可能致病性（P/LP）变异的个体的百分比，以及具有相关表型的已知单基因疾病基因中致病变异的诊断产量。
结果：总计，1953年，在10428名患者中，至少有一个P/LP变体。然后，792（7.6％）个体（包括759个个体在一个基因中包含一个P/LP变体，根据遗传模式，预测29个在不同基因中具有两种或更多种P/LP变体的个体和4个在ABCC6）中具有两种P/LP变体的个体处于一种或多种单基因疾病的风险中。最后,792名个体中的230名在EHR数据中表现出临床表型,以支持具有单基因原因的中风的诊断。该队列中最诊断的孟德尔卒中原因是常染色体显性遗传的脑动脉病伴皮质下梗死和白质脑病。年龄或家族史与患者首次症状性单基因卒中的发生率之间没有关系。
结论：回顾临床表型后，单基因卒中的发生率为2.2%。在患有缺血性卒中/TIA的成年患者中，孟德尔原因可能被遗漏的原因包括晚发作的卒中症状。结合常见的血管风险和没有突出的家族史。
方法：对通过CNSR-III招募的10428名患者的DNA样本进行了181个与卒中相关基因的靶向下一代测序。审查了来自电子健康记录（EHR）的遗传和临床数据，以完成诊断过程。我们评估了具有致病性或可能致病性（P/LP）变异的个体的百分比，以及具有相关表型的已知单基因疾病基因中致病变异的诊断产量。
结果：总计，1953年，在10428名患者中，至少有一个P/LP变体。然后，792（7.6％）个体（包括759个个体在一个基因中包含一个P/LP变体，根据遗传模式，预测29个在不同基因中具有两种或更多种P/LP变体的个体和4个在ABCC6）中具有两种P/LP变体的个体处于一种或多种单基因疾病的风险中。最后,792名个体中的230名在EHR数据中表现出临床表型,以支持具有单基因原因的中风的诊断。该队列中最诊断的孟德尔卒中原因是常染色体显性遗传的脑动脉病伴皮质下梗死和白质脑病。年龄或家族史与患者首次症状性单基因卒中的发生率之间没有关系。
结论：回顾临床表型后，单基因卒中的发生率为2.2%。在患有缺血性卒中/TIA的成年患者中，孟德尔原因可能被遗漏的原因包括晚发作的卒中症状。结合常见的血管风险和没有突出的家族史。
