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The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study.
BMC Med. 2008 Nov 05; 6:32.BM

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

Authors+Show Affiliations

Department of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USA. jlatoure@bu.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18986508

Citation

Latourelle, Jeanne C., et al. "The Gly2019Ser Mutation in LRRK2 Is Not Fully Penetrant in Familial Parkinson's Disease: the GenePD Study." BMC Medicine, vol. 6, 2008, p. 32.
Latourelle JC, Sun M, Lew MF, et al. The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study. BMC Med. 2008;6:32.
Latourelle, J. C., Sun, M., Lew, M. F., Suchowersky, O., Klein, C., Golbe, L. I., Mark, M. H., Growdon, J. H., Wooten, G. F., Watts, R. L., Guttman, M., Racette, B. A., Perlmutter, J. S., Ahmed, A., Shill, H. A., Singer, C., Goldwurm, S., Pezzoli, G., Zini, M., ... Myers, R. H. (2008). The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study. BMC Medicine, 6, 32. https://doi.org/10.1186/1741-7015-6-32
Latourelle JC, et al. The Gly2019Ser Mutation in LRRK2 Is Not Fully Penetrant in Familial Parkinson's Disease: the GenePD Study. BMC Med. 2008 Nov 5;6:32. PubMed PMID: 18986508.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study. AU - Latourelle,Jeanne C, AU - Sun,Mei, AU - Lew,Mark F, AU - Suchowersky,Oksana, AU - Klein,Christine, AU - Golbe,Lawrence I, AU - Mark,Margery H, AU - Growdon,John H, AU - Wooten,G Frederick, AU - Watts,Ray L, AU - Guttman,Mark, AU - Racette,Brad A, AU - Perlmutter,Joel S, AU - Ahmed,Anwar, AU - Shill,Holly A, AU - Singer,Carlos, AU - Goldwurm,Stefano, AU - Pezzoli,Gianni, AU - Zini,Michela, AU - Saint-Hilaire,Marie H, AU - Hendricks,Audrey E, AU - Williamson,Sally, AU - Nagle,Michael W, AU - Wilk,Jemma B, AU - Massood,Tiffany, AU - Huskey,Karen W, AU - Laramie,Jason M, AU - DeStefano,Anita L, AU - Baker,Kenneth B, AU - Itin,Ilia, AU - Litvan,Irene, AU - Nicholson,Garth, AU - Corbett,Alastair, AU - Nance,Martha, AU - Drasby,Edward, AU - Isaacson,Stuart, AU - Burn,David J, AU - Chinnery,Patrick F, AU - Pramstaller,Peter P, AU - Al-hinti,Jomana, AU - Moller,Anette T, AU - Ostergaard,Karen, AU - Sherman,Scott J, AU - Roxburgh,Richard, AU - Snow,Barry, AU - Slevin,John T, AU - Cambi,Franca, AU - Gusella,James F, AU - Myers,Richard H, Y1 - 2008/11/05/ PY - 2008/09/08/received PY - 2008/11/05/accepted PY - 2008/11/7/pubmed PY - 2009/5/19/medline PY - 2008/11/7/entrez SP - 32 EP - 32 JF - BMC medicine JO - BMC Med VL - 6 N2 - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. SN - 1741-7015 UR - https://www.unboundmedicine.com/medline/citation/18986508/The_Gly2019Ser_mutation_in_LRRK2_is_not_fully_penetrant_in_familial_Parkinson's_disease:_the_GenePD_study_ L2 - https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-6-32 DB - PRIME DP - Unbound Medicine ER -