Parkinson Disease via the LRRK2 Gene

Parkinson disease affects more than 1% of 55-year-olds and more than 3% of those older than 75 years. LRRK2-related Parkinson disease (Parkinson disease 8) is the most common genetic cause for both familial and sporadic Parkinson disease. The major symptoms of this disease include Parkinsonism, bradykinesia, rigidity, resting tremor and postural instability with onset at 50-65 years old and slow progression. Patients rarely present with cognitive decline and dementia. Patients have favorable response to pharmacologic replacement of dopamine (Bonifati et al., 2006. PubMed ID:16835587; Abeliovich and Gitler. 2016. PubMed ID: 27830778; Rassu et al. 2017. PubMed ID:28582422). Levetiracetam treatment also ameliorates symptoms (Rassu et al. 2019. PubMed ID: 31560168). In addition, other potential therapeutics for LRRK2-related Parkinson disease have been investigated, for example, the development of small molecules to inhibit toxic gain of function of LRRK2 kinase activity (Kelly et al. 2018. PubMed ID: 30048714; Shihabuddin et al. 2018. PubMed ID: 30381429).

LRRK2-related Parkinson disease (Parkinson disease 8) is inherited in autosomal dominant manner with incomplete penetrance. Pathogenic variants in LRRK2 include nonsense, missense, splicing, and small frameshift deletion/duplication variants. No large deletions/duplications in the LRRK2 locus have been reported to date (Human Gene Mutation Database). The vast majority of pathogenic variants are missense. The most common variant, p.Gly2019Ser in the kinase domain, is a founder variant with incomplete penetrance in patients of Ashkenazi Jewish and North African Berbers ancestry. The allele frequency of p.Gly2019Ser in people of Ashkenazi Jewish ancestry is 0.84% (Bonifati et al. 2006. PubMed ID:16835587; Goldwurm et al. 2007. PubMed ID:17215492; Nickels et al. 2019. PubMed ID: 31621607, gnomAD). Cell model studies demonstrated that the Gly2019Ser variant is sufficient to cause neurodegeneration of dopaminergic neurons (Cresto et al. 2019. PubMed ID: 31605779). Another founder variant is p.Arg1441Cys which is found in the Basque, southern Italian, and Belgian populations. De novo pathogenic variants in LRRK2 may occur (Saunders-Pullman et al. 2019. PubMed ID:20301387).

LRRK2 encodes leucine-rich repeat kinase 2. This leucine-rich repeat kinase 2 is a member of Roco superfamily proteins, a novel multi-domain family of Ras-like G-proteins. In vitro cell expression and animal model studies demonstrate that defects in LRRK2 lead to defective endosome-to-lysosome trafficking, accumulation of abnormal lysosomal structures, and a reduction in the number of neurite pro­cesses in neurons (Biosa et al. 2013. PubMed ID:23241358; Abeliovich and Gitler 2016. PubMed ID: 27830778; Rassu et al. 2017. PubMed ID: 31560168).

LRRK2 causative variants are detected in ~1-2% of patients with Parkinson disease in general. However, in some populations, its most common pathogenic variant, Gly2019Ser, has been detected in 5 to 6% of familial Parkinson disease, and 1 to 2 % of sporadic Parkinson disease (Bonifati et al. 2006. PubMed ID:16835587).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the LRRK2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).