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

Jeanne C. Latourelle, Mei Sun, Mark F. Lew, Oksana Suchowersky, Christine Klein, Lawrence I. Golbe, Margery H. Mark, John H. Growdon, G. Frederick Wooten, Ray L. Watts, Mark Guttman, Brad A. Racette, Joel S. Perlmutter, Anwar Ahmed, Holly A. Shill, Carlos Singer, Stefano Goldwurm, Gianni Pezzoli, Michela Zini, Marie H. Saint-HilaireAudrey E. Hendricks, Sally Williamson, Michael W. Nagle, Jemma B. Wilk, Tiffany Massood, Karen W. Huskey, Jason M. Laramie, Anita L. DeStefano, Kenneth B. Baker, Ilia Itin, Irene Litvan, Garth Nicholson, Alastair Corbett, Martha Nance, Edward Drasby, Stuart Isaacson, David J. Burn, Patrick F. Chinnery, Peter P. Pramstaller, Jomana Al-Hinti, Anette T. Moller, Karen Ostergaard, Scott J Sherman, Richard Roxburgh, Barry Snow, John T. Slevin, Franca Cambi, James F. Gusella, Richard H. Myers

Research output: Contribution to journalArticle

70 Citations (Scopus)

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.

Original languageEnglish (US)
Article number32
JournalBMC Medicine
Volume6
DOIs
StatePublished - Nov 5 2008

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Leucine
Parkinson Disease
Phosphotransferases
Penetrance
Mutation

ASJC Scopus subject areas

  • Medicine(all)

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Latourelle, J. C., Sun, M., Lew, M. F., Suchowersky, O., Klein, C., Golbe, L. I., ... 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

The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease : The GenePD study. / Latourelle, Jeanne C.; Sun, Mei; Lew, Mark F.; Suchowersky, Oksana; Klein, Christine; Golbe, Lawrence I.; Mark, Margery H.; Growdon, John H.; Wooten, G. Frederick; Watts, Ray L.; Guttman, Mark; Racette, Brad A.; Perlmutter, Joel S.; Ahmed, Anwar; Shill, Holly A.; Singer, Carlos; Goldwurm, Stefano; Pezzoli, Gianni; Zini, Michela; Saint-Hilaire, Marie H.; Hendricks, Audrey E.; Williamson, Sally; Nagle, Michael W.; Wilk, Jemma B.; Massood, Tiffany; Huskey, Karen W.; Laramie, Jason M.; DeStefano, Anita L.; Baker, Kenneth B.; Itin, Ilia; Litvan, Irene; Nicholson, Garth; Corbett, Alastair; Nance, Martha; Drasby, Edward; Isaacson, Stuart; Burn, David J.; Chinnery, Patrick F.; Pramstaller, Peter P.; Al-Hinti, Jomana; Moller, Anette T.; Ostergaard, Karen; Sherman, Scott J; Roxburgh, Richard; Snow, Barry; Slevin, John T.; Cambi, Franca; Gusella, James F.; Myers, Richard H.

In: BMC Medicine, Vol. 6, 32, 05.11.2008.

Research output: Contribution to journalArticle

Latourelle, JC, Sun, M, Lew, MF, Suchowersky, O, Klein, C, Golbe, LI, Mark, MH, Growdon, JH, Wooten, GF, Watts, RL, Guttman, M, Racette, BA, Perlmutter, JS, Ahmed, A, Shill, HA, Singer, C, Goldwurm, S, Pezzoli, G, Zini, M, Saint-Hilaire, MH, Hendricks, AE, Williamson, S, Nagle, MW, Wilk, JB, Massood, T, Huskey, KW, Laramie, JM, DeStefano, AL, Baker, KB, Itin, I, Litvan, I, Nicholson, G, Corbett, A, Nance, M, Drasby, E, Isaacson, S, Burn, DJ, Chinnery, PF, Pramstaller, PP, Al-Hinti, J, Moller, AT, Ostergaard, K, Sherman, SJ, Roxburgh, R, Snow, B, Slevin, JT, Cambi, F, Gusella, JF & Myers, RH 2008, 'The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: The GenePD study', BMC Medicine, vol. 6, 32. https://doi.org/10.1186/1741-7015-6-32
Latourelle, Jeanne C. ; Sun, Mei ; Lew, Mark F. ; Suchowersky, Oksana ; Klein, Christine ; Golbe, Lawrence I. ; Mark, Margery H. ; Growdon, John H. ; Wooten, G. Frederick ; Watts, Ray L. ; Guttman, Mark ; Racette, Brad A. ; Perlmutter, Joel S. ; Ahmed, Anwar ; Shill, Holly A. ; Singer, Carlos ; Goldwurm, Stefano ; Pezzoli, Gianni ; Zini, Michela ; Saint-Hilaire, Marie H. ; Hendricks, Audrey E. ; Williamson, Sally ; Nagle, Michael W. ; Wilk, Jemma B. ; Massood, Tiffany ; Huskey, Karen W. ; Laramie, Jason M. ; DeStefano, Anita L. ; Baker, Kenneth B. ; Itin, Ilia ; Litvan, Irene ; Nicholson, Garth ; Corbett, Alastair ; Nance, Martha ; Drasby, Edward ; Isaacson, Stuart ; Burn, David J. ; Chinnery, Patrick F. ; Pramstaller, Peter P. ; Al-Hinti, Jomana ; Moller, Anette T. ; Ostergaard, Karen ; Sherman, Scott J ; Roxburgh, Richard ; Snow, Barry ; Slevin, John T. ; Cambi, Franca ; Gusella, James F. ; Myers, Richard H. / The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease : The GenePD study. In: BMC Medicine. 2008 ; Vol. 6.
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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.",
author = "Latourelle, {Jeanne C.} and Mei Sun and Lew, {Mark F.} and Oksana Suchowersky and Christine Klein and Golbe, {Lawrence I.} and Mark, {Margery H.} and Growdon, {John H.} and Wooten, {G. Frederick} and Watts, {Ray L.} and Mark Guttman and Racette, {Brad A.} and Perlmutter, {Joel S.} and Anwar Ahmed and Shill, {Holly A.} and Carlos Singer and Stefano Goldwurm and Gianni Pezzoli and Michela Zini and Saint-Hilaire, {Marie H.} and Hendricks, {Audrey E.} and Sally Williamson and Nagle, {Michael W.} and Wilk, {Jemma B.} and Tiffany Massood and Huskey, {Karen W.} and Laramie, {Jason M.} and DeStefano, {Anita L.} and Baker, {Kenneth B.} and Ilia Itin and Irene Litvan and Garth Nicholson and Alastair Corbett and Martha Nance and Edward Drasby and Stuart Isaacson and Burn, {David J.} and Chinnery, {Patrick F.} and Pramstaller, {Peter P.} and Jomana Al-Hinti and Moller, {Anette T.} and Karen Ostergaard and Sherman, {Scott J} and Richard Roxburgh and Barry Snow and Slevin, {John T.} and Franca Cambi and Gusella, {James F.} and Myers, {Richard H.}",
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TY - JOUR

T1 - The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease

T2 - 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.

PY - 2008/11/5

Y1 - 2008/11/5

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.

AB - 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.

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