Submission Details

LRRK2 was first reported in relation to autosomal-dominant Parkinson´s disease in 2004 (Paisan-Ruiz et al., PMID: 15541308; Zimprich et al., PMID: 15541309). Parkinson´s disease is a progressive degenerative disorder of the central nervous system characterized by loss of dopamine producing neurons in the substantia nigra, and Lewy bodies in the substantia nigra and locus coeruleus are found in most cases. In patients with pathogenic LRRK2 variants, the typical Parkinson´s disease pathology with Lewy bodies can often been found (Ross et al. 2006, PMID: 16437559; Kalia et al. 2015, PMID: 25401511) but tau-immunopositive neurofibrillary tangles have also been reported (Rajput et al. 2006, PMID: 17060589). Signs and symptoms of Parkinson´s disease include tremor which is most pronounced during rest, muscle rigidity, slowing of the voluntary movements (bradykinesia), a tendency to fall back (postural instability). Several clearly pathogenic, missense variants have been reported in >1000 probands in >100 publications (for review see Trinh et al. 2018, PMID: 30357936, www.mdsgene.org) of which five publications are included in this curation. The most frequently found mutation is c.6055G>A/p.G2019S (NM_198578, ClinVar ID: 1940). The additional evidence from the literature was not included in this curation because the maximum score for genetic evidence (12 pts.) has been reached. Although the disease follows a clearly dominant mode of inheritance with age-dependent reduced penetrance, homozygous carriers of pathogenic variants have been reported with comparable phenotype to heterozygous carriers (Ishihara et al. 2006, PMID: 16966502). The mechanism of pathogenicity appears to be gain-of-function (GOF) with augmented kinase activity (West et al. 2005, PMID: 16269541). The gain-of-function mechanism is also underlined by the lack of Parkinson´s disease in carriers of truncating variants (Blauwendraat et al. 2018, PMID: 30039155). This gene-disease association is further supported by recurrent experimental evidence including animal models, in-vitro functional assays, and patient-derived cells (Giasson et al. 2006, PMID: 16437584; Jaleel et al. 2007, PMID: 17447891; Luzón-Toro et al. 2007, PMID: 17584768; Liu et al. 2008, PMID: 18258746; Fraser et al. 2016, PMID: 26865512; Boecker et al. 2021, PMID: 33765413). In summary, pathogenic variants in LRRK2 are definitively causing autosomal-dominant Parkinson´s disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Parkinson’s Disease Gene Curation Expert Panel on May 3, 2021.