Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Lund, Sweden.
Lund University, Department of Experimental Medical Science, Lund, Sweden.
Parkinsonism Relat Disord. 2019 Sep;66:158-165. doi: 10.1016/j.parkreldis.2019.07.032. Epub 2019 Jul 31.
To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients.
The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database.
A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined.
In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives.
在一个超过瑞典预估帕金森病（PD）患者人数 10%的系列中，确定已知导致常染色体显性 PD 的突变频率。
瑞典帕金森病遗传学网络作为一个国家性的多中心临床研究人员联盟成立，这些研究人员总共可以获得来自 2206 名 PD 患者的 DNA；85.4%的患者来自基于人群的研究。对 SNCA（重复/三倍体，p.Ala30Pro，p.Ala53Thr）和 LRRK2（p.Asn1437His，p.Arg1441His，p.Tyr1699Cys，p.Gly2019Ser，p.Ile2020Thr）中的已知致病性突变进行集中分析。我们将这些突变在瑞典患者中的频率与已发表的 PD 系列和 gnomAD 数据库进行了比较。
21.6%的参与者报告有一级和/或二级亲属的 PD 家族史。12 名患者（0.54%）携带 LRRK2 p.(Gly2019Ser)突变，1 名患者（0.045%）携带 SNCA 重复。在匹配的瑞典对照组中，LRRK2 p.(Gly2019Ser)携带者的频率为 0.11%，在 gnomAD 中也相似为 0.098%，但在 gnomAD 中不同种族之间存在显著差异，与所有其他人相比，阿什肯纳兹犹太人的频率高出 42 倍。
从相对的角度来看，LRRK2 p.(Gly2019Ser)变体是瑞典或国际 PD 患者以及 gnomAD 中最常见的突变。SNCA 重复是检查的突变中第二常见的。然而，从绝对的角度来看，这些常染色体显性 PD 基因中的已知致病性变体通常非常罕见，只能解释 PD 家族聚集的一小部分。其他遗传和环境机制可能解释了 PD 在近亲中经常同时发生的现象。
