Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers
Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers
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DOI：
10.1212/wnl.0b013e318245f476
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发表时间：
2012-02-01
期刊：
影响因子：
9.9
通讯作者：
Brice, A.
中科院分区：
文献类型：
--
作者：
Anheim, M.;Elbaz, A.;Brice, A.
目的：葡萄糖脑苷酶(GBA)基因突变是帕金森病(PD)的重要危险因素。GBA突变携带者的PD外显率是遗传咨询的关键问题，特别是对高谢病患者的亲属来说，目前尚不清楚。我们的目的是在GBA突变携带者的家族性研究中估计帕金森病的外显率。方法：通过法国帕金森病遗传研究组招募有家族性帕金森病的先证者。对先证者及其亲属的所有Gba外显子进行了测序。结果：在525例家族性帕金森病先证者中，24例(4.6%)为GBA基因突变携带者。在他们的256名亲属中，43名(16.8%)患有帕金森病，32名受影响的亲属中有26名为突变携带者；213名亲属没有帕金森病，71名未受影响的亲属中有31名为突变携带者。在显性模型下，50、60、70和80岁时的外显率分别为7.6%、13.7%、21.4%和29.7%。N370S携带者、L444P携带者和罕见突变携带者在70岁时的外显率无显著差异。结论：本研究获得的GBA携带者的外显率相对较高，应认为GBA是外显性降低的显性原因基因，应考虑在GD患者亲属和GBA相关PD患者的遗传咨询中考虑GBA。神经病学(R)2012；78：417-420
Objective: Glucocerebrosidase (GBA) gene mutations represent a strong risk factor for Parkinson disease (PD). PD penetrance in GBA mutation carriers, which represents a key issue for genetic counseling, especially for relatives of patients with Gaucher disease (GD), is unknown. Our objective was to estimate PD penetrance in a familial study of GBA mutation carriers.Methods: Probands with familial PD were recruited through the French Parkinson Disease Genetic Study Group. All GBA exons were sequenced in probands and their relatives. To estimate the age-specific cumulative PD risk (i.e., penetrance) in GBA mutation carriers, we used the proband's phenotype exclusion likelihood method and corrected for selection of familial cases by considering the status of one affected relative per family as unknown.Results: Of 525 probands with familial PD, 24 (4.6%) were GBA mutation carriers. Of their 256 relatives, 43 (16.8%) had PD and 26 of 32 affected relatives tested for GBA mutations were mutation carriers; 213 relatives did not have PD and 31 of 71 of unaffected relatives tested for GBA mutations were mutation carriers. Under a dominant model, penetrance was estimated as 7.6%, 13.7%, 21.4%, and 29.7% at 50, 60, 70, and 80 years, respectively. There was no significant difference in penetrance at 70 years between N370S carriers, L444P carriers, and carriers of rarer mutations.Conclusion: The relatively high penetrance estimate in GBA carriers obtained in this study should lead to consideration of GBA as a dominant causal gene with reduced penetrance and should be taken into account for genetic counseling in relatives of patients with GD and patients with GBA-associated PD. Neurology (R) 2012; 78: 417-420