Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort
Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort
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DOI：
10.3389/fneur.2020.00682
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发表时间：
2020-07-28
影响因子：
3.4
通讯作者：
Brice, Alexis
中科院分区：
文献类型：
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作者：
Lesage, Suzanne;Houot, Marion;Brice, Alexis
LRRK2、SNCA和VPS35与常染色体显性遗传性帕金森病(PD)明确相关。我们评估了一组法国多中心PD患者中LRRK2、SNCA和VPS35突变的患病率及其相关的临床特征。自1990年以来收集了1805例指征病例(592例常染色体显性遗传和1213例孤立病例)的人口学和临床数据。对所有先证者进行LRRK2Gly2019Ser TaqMan筛查。在没有这种突变的情况下，对这三个基因的编码序列进行Sanger测序和/或下一代测序。根据发病年龄、家族史、种族来源和临床特征对这三个基因的数据进行分析。我们确定了160例(8.9%)已知的致病变异：138例致病LRRK2变异(7.6%)，包括136例Gly2019Ser突变，19例SNCA点突变或基因组重排(1.1%)，3例VPS35Asp620Asn突变(0.16%)。家族性突变频率高于孤立病例，符合常染色体显性遗传(12.0vs.7.3%；OR1.7，95%CI[1.2-2.4]，p=0.001)。携带LRRK2突变的帕金森病患者更有可能有更高的迟发性帕金森病发病率(>；50岁；OR 1.5，95%CI[1.0-2.1]，p=0.03)，而携带SNCA突变的患者往往发病年龄较早(
LRRK2, SNCA, andVPS35are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence ofLRRK2, SNCA, andVPS35mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays forLRRK2Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenicLRRK2variants (7.6%), including 136 with the Gly2019Ser mutation, 19 withSNCApoint mutations or genomic rearrangements (1.1%), and three with theVPS35Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4],p= 0.001). PD patients withLRRK2variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1],p= 0.03), whereas those withSNCAmutations tended to have earlier age at onset disease (