The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's Disease: the GenePD study

Department of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USA.
BMC Medicine (Impact Factor: 7.25). 12/2008; 6(1):32. DOI: 10.1186/1741-7015-6-32
Source: PubMed


We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.
A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.
Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.
Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

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    • "It also appears to be varied between the ethnicities and is higher in Arab Berber than Ashkenazi Jews.71,72 The penetrance reported in initial family-based studies may be overestimated, and the corrected overall penetrance is 67%.73 "
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    • "Occurrence of LRRK2 mutations in apparently sporadic patients and in healthy control individuals49,56 suggests a reduced penetrance. Estimations of the penetrance for G2019S range from 32% to 74%, depending on the familial background of the families analyzed.49,55,60 G2019S was also found in homozygosity, but with no difference in clinical phenotype compared with heterozygous carriers.57 "
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    • "As an example, mutations in the LRRK2 gene appear to account for 1-2% of sporadic PD. There also appear to be unknown factors that influence penetrance of LRRK2 mutations that may account for increased prevalence of non-LRRK2 PD phenotypes found in LRRK2 mutation-bearing families (Latourelle, et al., 2008). These potential influences on the PD cellular phenotype would not be expressed in a cybrid model. "
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