REVIEW Genotype-Phenotype Relations for the Parkinson’s Disease Genes Parkin, PINK1, DJ1: MDSGene Systematic Review Meike Kasten, MD,1,2 Corinna Hartmann, MD,1 Jennie Hampf, MD,1 Susen Schaake, BSc,1 Ana Westenberger, PhD,1 Eva-Juliane Vollstedt, MD,1 Alexander Balck, MD,1 Aloysius Domingo, MD, PhD,1 Franca Vulinovic, PhD,1 Marija Dulovic, MD, PhD,1 Ingo Zorn,3 Harutyun Madoev,1 Hanna Zehnle,1 Christina M. Lembeck, BSc,1 Leopold Schawe, BSc,1 Jennifer Reginold, BSc,4 Jana Huang, BHS,4 Inke R. Konig,€ PhD,5 Lars Bertram, MD,3,6 Connie Marras, MD, PhD,4 Katja Lohmann, PhD,1 Christina M. Lill, MD, MSc,1 and Christine Klein, MD1* 1Institute of Neurogenetics, University of Lubeck,€ Lubeck,€ Germany 2Department of Psychiatry and Psychotherapy, University of Lubeck,€ Lubeck,€ Germany 3Lubeck€ Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lubeck,€ Lubeck,€ Germany 4The Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson’s Disease, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada 5Institute of Medical Biometry and Statistics, University of Lubeck,€ Lubeck,€ Germany 6School of Public Health, Faculty of Medicine, Imperial College London, London, UK ABSTRACT: This first comprehensive MDSGene early onset (median age at onset of ~30 years for car- review is devoted to the 3 autosomal recessive Parkin- riers of at least 2 mutations in any of the 3 genes) of an son’s disease forms: PARK-Parkin, PARK-PINK1, and overall clinically typical form of PD with excellent treat- PARK-DJ1. It followed MDSGene’s standardized data ment response, dystonia and dyskinesia being relatively extraction protocol and screened a total of 3652 cita- common and cognitive decline relatively uncommon. tions and is based on fully curated phenotypic and However, when comparing actual data with common genotypic data on >1100 patients with recessively expert knowledge in previously published reviews, we inherited PD because of 221 different disease-causing detected several discrepancies. We conclude that sys- mutations in Parkin, PINK1,orDJ1. All these data are tematic reporting of phenotypes is a pressing need in also available in an easily searchable online database light of increasingly available molecular genetic testing (www.mdsgene.org), which also provides descriptive and the emergence of first gene-specific therapies summary statistics on phenotypic and genetic data. entering clinical trials. VC 2018 International Parkinson Despite the high degree of missingness of phenotypic and Movement Disorder Society features and unsystematic reporting of genotype data in the original literature, the present review recapitulates Key Words: Parkin; PRKN; PARK2; PINK1; PARK7; many of the previously described findings including DJ1; Parkinson’s disease; genetics ------------------------------------------------------------ *Correspondence to: Christine Klein, MD, Institute of Neurogenetics, University of Lubeck,€ Maria-Goeppert-Str. 1, 23562 Lubeck,€ Germany; The increasing cost-efficiency of genetic testing and [email protected] recent technological advances including next- Meike Kasten, Corinna Hartmann, Jennie Hampf, Susen Schaake, generation sequencing techniques have led to a sub- Christina M. Lill, and Christine Klein contributed equally to this work. stantial increase in the number of publications and Relevant conflicts of interest/financial disclosures: There is no finan- cial conflict of interest. the spectrum of reported mutations potentially causa- Funding agencies: The study was supported by the Movement Disorder tive for human diseases. This growing body of data is Society (to C.K., C.M., C.M.L., and L.B.), by the Deutsche Forschungs- becoming increasingly difficult to follow and inter- gemeinschaft (FOR2488; to C.K., M.K., A.W., K.L., L.B., I.R.K., and pret. The vast majority of reviews on inherited dis- C.M.L.), by the Possehl Foundation (to C.M.L.), and by intramural funds from the University of Luebeck (to C.K.). eases including movement disorders are narrative, Received: 20 October 2017; Revised: 12 January 2018; Accepted: 16 that is, they provide a qualitative and thereby subjec- January 2018 tive and selective account of the available literature. To date, very few systematic review articles are avail- Published online 11 April 2018 in Wiley Online Library 1 2 (wileyonlinelibrary.com). DOI: 10.1002/mds.27352 able (eg, see references and )thatprovideacase- 730 Movement Disorders, Vol. 33, No. 5, 2018 MDSGene REVIEW: Parkin, PINK1, DJ1 by-case unbiased account of the entire published Titles, abstracts, and, where applicable, full texts of English-language literature by quantifying all avail- peer-reviewed original articles in English and pub- able data. lished until September 20, 2017, were screened for Causative mutations in the autosomal-recessive Par- inclusion in the systematic review. Only articles kinson’s disease (PD) genes PRKN (commonly and reporting at least 1 patient likely harboring biallelic therefore also in this article referred to as Parkin), Parkin, PINK1,orDJ1 mutations were selected. In PINK1, and PARK7 (commonly and therefore also in addition, reviews on any of the 3 disease genes of this article referred to as DJ1) account for approxi- interest were screened for additional data and further, mately 13% of early-onset PD, that is, PD occurring potentially eligible articles. For an overview of the lit- 3 before the age of 40 years. In this study, we present erature search as well as the filtering procedure, see the first systematic MDSGene review and devote it to Supplementary Figure 1A. A list of all eligible articles autosomal-recessive PD across the 3 disorders: PARK- can be found in the Supplementary Methods 1. Parkin, PARK-PINK1, and PARK-DJ1 (nomenclature according to the recommendations of the MDS Task Inclusion and Exclusion Criteria for Patients Force Classification and Nomenclature of Genetic and Genetic Variants Movement Disorders).4 Our group has recently devel- Because this review is limited to genes following oped and launched the Movement Disorder Society autosomal-recessive transmission, only patients carrying Genetic mutation database (MDSGene; http://www. 2 or more mutations in the same gene were included. mdsgene.org).5 MDSGene aims to provide a compre- Genetic variants across all 3 genes were part of our sys- hensive online resource linking reported genetic muta- tematic assessment. Variants were excluded if they had tions with movement disorder phenotypes and other a minor allele frequency (MAF) 1% based on the demographic and clinical information. This review fol- ethnicity with the maximal MAF in the ExAC Browser lows MDSGene’s standardized data extraction proto- (http://exac.broadinstitute.org), dbSNP (http://www. col optimized for hereditary movement disorders and ncbi.nlm.nih.gov/snp/), and/or in at least 100 unaf- (1) presents an overview on the currently available phenotypic and genotypic data on autosomal recessive fected control individuals screened for the variant of PD, (2) assesses the pathogenicity of reported poten- interest in the respective publication. Where available, tially causative mutations, (3) compares published clinical data were extracted for all mutation carriers data across the 3 genes and provides stratified analyses who had definite or probable PD designated as such in in selected patient subgroups, (4) evaluates the extent the respective publication or who were described to and potential impact of missing data on the interpreta- show bradykinesia and at least 1 additional cardinal tion of the results, and (5) identifies potential conse- parkinsonian sign, that is, resting tremor, rigidity, and quences for genetic counseling in clinical practice, as postural instability. This included patients originating well as resulting new research leads. from multiplex as well as simplex families. Methods Data Collection Process We applied the above-described MDSGene data MDSGene extraction protocol to all eligible articles. For each The literature search and data extraction protocol publication, data on demographic, genetic, and clinical have been developed for the generation and mainte- variables were extracted (see Supplementary Table 2 nance of MDSGene, a database that summarizes and for the list of extracted variables). Information was quantifies genetic and phenotypic data from the litera- obtained from the original or related (ie, previously or ture for hereditary movement disorders.5 Data col- subsequently published) articles referring to the same lected for this review have been posted on MDSGene patients. Phenotypic variables comprised clinical signs (available at http://www.mdsgene.org). and symptoms, levodopa response, and information on different motor and nonmotor scales. Physical loca- Literature Search and Eligibility Criteria tion, genomic, coding, and protein nomenclature as We performed a systematic literature search for pub- well as genotype and zygosity (genotype) were col- lications on PD patients with Parkin, PINK1, and DJ1 lected for all mutations. Missing nomenclature was mutations using the National Center for Biotechnol- curated from the given information wherever possible ogy Information’s PubMed database (https://www. using the Ensembl (http://www.ensembl.org/)6 and ncbi.nlm.nih.gov/pubmed) based on standardized Mutation Taster (http://www.mutationtaster.org/)7 data- search terms (Supplementary Table 1). An