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Penetrance of LRRK2 mutations in familial Parkinson disease

Latourelle JC et al. (2008) The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study. BMC Med 6: 32

The most common genetic cause of Parkinson disease (PD) is a mutation in the leucine-rich repeat kinase 2 (LRRK2) gene that causes a Gly2019Ser substitution, which is associated with 5–6% of familial PD cases and 1–2% of idiopathic cases. Wide variations in penetrance estimates of such mutations have been reported. Now, as part of the GenePD study, Latourelle et al. report on lifetime penetrance of LRRK2 mutations in familial PD in a large study sample.

The team studied 903 patients with PD and 58 unaffected individuals from a total of 509 families, in which at least two members had PD, plus 126 randomly selected patients with PD and 197 control individuals. All participants were screened for LRRK2 mutations; carriers of such mutations (54 individuals with Gly2019Ser mutations and 4 with Arg1441Cys mutations) were identified in 31 families, whereas no such mutations were found in the control group or healthy relatives of patients with PD.

The estimated penetrance of Gly2019Ser mutations was 67% at the maximum observed age range (90–94 years) in this sample of familial PD, compared with an estimated penetrance of 33% in randomly sampled cases from a previous study.

These results indicate that other risk factors might contribute to the onset of PD, irrespective of Gly2019Ser status. Increased penetrance in familial samples might be explained by inheritance of other susceptibility factors in family members.

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Penetrance of LRRK2 mutations in familial Parkinson disease. Nat Rev Neurol 5, 120 (2009).

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