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


CONCLUSIONS
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.
Latourelle
Jeanne C
JC
Department of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USA. jlatoure@bu.edu
Sun
Mei
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Lew
Mark F
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Suchowersky
Oksana
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Klein
Christine
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Golbe
Lawrence I
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Mark
Margery H
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Growdon
John H
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Wooten
G Frederick
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Watts
Ray L
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Guttman
Mark
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Racette
Brad A
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Perlmutter
Joel S
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Ahmed
Anwar
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Shill
Holly A
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Singer
Carlos
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Goldwurm
Stefano
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Pezzoli
Gianni
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Zini
Michela
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Saint-Hilaire
Marie H
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Hendricks
Audrey E
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Williamson
Sally
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Nagle
Michael W
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Wilk
Jemma B
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Massood
Tiffany
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Huskey
Karen W
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Laramie
Jason M
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DeStefano
Anita L
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Baker
Kenneth B
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Itin
Ilia
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Litvan
Irene
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Nicholson
Garth
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Corbett
Alastair
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Nance
Martha
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Drasby
Edward
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Isaacson
Stuart
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Burn
David J
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Chinnery
Patrick F
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Pramstaller
Peter P
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Al-hinti
Jomana
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Moller
Anette T
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Ostergaard
Karen
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Sherman
Scott J
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Roxburgh
Richard
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Snow
Barry
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Slevin
John T
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Cambi
Franca
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Gusella
James F
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Myers
Richard H
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D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005998:Glycine / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D019683:Penetrance; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011897:Random Allocation; D012694:Serine / Q000235:genetics*; D012737:Sex Factors
D012694:Serine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005998:Glycine