Parkinson Disease and Complex Parkinsonism
Gene: LRRK2
Monoallelic mutations are the most common known genetic cause of late-onset PD and are found in both autosomal dominant and sporadic PD. However, caution as reduced penetrance. PMID: 27090875 states - To date, more than 100 distinct missense and non-sense mutations have been reported in LRRK2 (Rubio et al. 2012), however, only for a small minority is there overwhelming proof of pathogenicity (p.R1441C/G/H, p.Y1699C, p.S1761R, p.I2012T,p.G2019S, and p.I2020T) (Healy et al. 2008, Aasly et al. 2010,Nuytemans et al. 2010, Bardien et al. 2011, Lorenzo-Betancoret al. 2012). These pathogenic modi_cations are clustered in exons encoding the Ras of complex proteins (ROC), C-terminusof ROC, or kinase domains of the protein.The most well-studied mutation, p.G2019S, is common across many populations and has been identi_ed in up to 42 percent of familial cases, depending on the ethnic background. (from Singleton 2016 medscape) - The penetrance of LRRK2 mutations has been a topic of intense study and debate. The most parsimonious models employ age-based penetrance estimates, which suggest that the G2019S mutation has a penetrance of 28 percent at age 59 years, 51 percent at age 69 years, and 74 percent at age 79 years. For the R1441G change, a mutation with high prevalence in the Basque population, penetrance estimates are 13 percent at age 65 years, increasing to 83 percent at age 80 years.Penetrance estimates have not been established for other LRRK2 mutations. Discussed with HH, at NHNN they report only the pathogenic variants p.G2019S, R1441G.Created: 14 Dec 2016, 5:27 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
Mode of pathogenicity
Other - please provide details in the comments
Mutations in LRRK2 are the most common genetic cause of both familial and sporadic PD, with at least 6 pathogenic mutations in the gene (reviewed by PMID:25391693). The most common mutation of the LRRK2 gene is G2019S, which is probably responsible for up-regulation of LRRK2 activity.Created: 10 Nov 2016, 3:32 p.m.
Comment on list classification: Discussed internally and make green. Known pathogenic variants to be curated to add to the teiring pipeline.Created: 15 Dec 2016, 9:54 a.m.
Comment on list classification: Changed to amber as unsure due to only known pathogenic variants in this gene should be reported.Created: 14 Dec 2016, 5:47 p.m.
Comment on list classification: Unsure due to incomplete penetrance, which may be age-related. Multiple different variants have been reported in this gene in families from different ethnicities. It is in the prior genetic testing for the Early onset and familial Parkinson's Disease eligibility statement.Created: 3 Nov 2016, 12:57 p.m.
Comment on mode of pathogenicity: An activating variant has been reported.Created: 28 Oct 2016, 12:53 p.m.
Comment on list classification: A founder mutation was reported in Basque patients.Created: 28 Oct 2016, 12:52 p.m.
Information from the NHNN Neurogenetics genetic testing manual: "It has now been shown that mutations in LRRK2 are associated with reduced penetrance, thereby gene carriers may be unaffected and a clear autosomal dominant family history may not be obvious. There is also accumulating but unproven evidence that single hit mutations in the recessive genes may contribute to an individual’s parkinsonian syndrome. Therefore, giving guidance on gene testing is complicated."Created: 10 Jun 2016, 10:35 a.m.
Comment on list classification: Is on the Parkinson's Disease NGS Panel in the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual.Created: 10 Jun 2016, 9:26 a.m.
Publications for LRRK2 were set to 25391693;27090875;28395805;28395804;28395803;28395802
19th Dec 2016: panel revised according to expert review and further curation.
This gene has been classified as Green List (High Evidence).
Mode of pathogenicity for LRRK2 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
This gene has been classified as Green List (High Evidence).
This gene has been classified as Amber List (Moderate Evidence).
Publications for LRRK2 were set to 25391693;27090875
This gene has been classified as Amber List (Moderate Evidence).
This gene has been classified as Green List (High Evidence).
Publications for LRRK2 were set to 25391693
This gene has been classified as Amber List (Moderate Evidence).
Mode of pathogenicity for LRRK2 was changed to Other - please provide details in the comments
This gene has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
LRRK2 was created by ellenmcdonagh
LRRK2 was added to Parkinson Disease and Complex Parkinsonismpanel. Sources: Radboud University Medical Center, Nijmegen,Expert,Illumina TruGenome Clinical Sequencing Services,UKGTN,Eligibility statement prior genetic testing