MDSGene update and expansion: Clinical and genetic spectrum of LRRK2 variants in Parkinson's disease

Pathogenic variants in the LRRK2 gene are one of the most commonly identifiable monogenic causes of Parkinso[n]s disease (PD, PARK-LRRK2). This systematic MDSGene literature review comprehensively summarizes published demographic, clinical, and genetic findings related to potentially pathogenic LRRK2 variants (https://www.mdsgene.org/). Recent insights on LRRK2s kinase activity have been incorporated for pathogenicity scoring. Data on 7,885 individuals with 292 different variants were curated, including 3,296 patients with PD carrying 205 different potentially disease-causing LRRK2 variants. The initial MDSGene review covered only 724 patients carrying 23 different LRRK2 variants. Missingness of phenotypic data in the literature was high, hampering the identification of detailed genotype-phenotype correlations. Notably, the median age at onset in the patients with available information was 56 years, with approximately one-third having PD onset <50 years. Tremor was the most frequently reported initial symptom and more frequent than reported in other dominantly inherited forms of PD. Of the 205 potentially disease-causing variants, 14 (6.8%) were classified as pathogenic, 8 (3.9%) as likely pathogenic, and the remaining 183 (89.3%) as variants of uncertain significance (VUS). The pathogenic p.G2019S variant was the most frequent pathogenic variant, followed by p.R1441G and p.R1441C, accounting for >80% of patients, with Tunisia, Spain, and Italy contributing about half of patients. This systematic review represents the largest database on PARK-LRRK2 to date and provides an important resource to improve precision medicine. Given their high frequency, a better interpretation of the pathogenicity of VUS is needed for selection and stratification of patients in clinical trials.