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The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of\n                    <jats:italic>PRKN<\/jats:italic>\n                    -PD was also assessed. Among 133 variants in index cases (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009145, 12.3%), followed by the p.R275W substitution (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4\u2009\u00b1\u20091.6 years or a 4.7\u2009\u00b1\u20091.6 years earlier age at onset of\n                    <jats:italic>PRKN<\/jats:italic>\n                    -PD respectively (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of\n                    <jats:italic>PRKN<\/jats:italic>\n                    -PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in\n                    <jats:italic>PRKN<\/jats:italic>\n                    -PD. Our findings on the relationship between the type of variant in\n                    <jats:italic>PRKN<\/jats:italic>\n                    and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.\n                  <\/jats:p>","DOI":"10.1038\/s41531-024-00677-3","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T14:02:14Z","timestamp":1711720934000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Genotype\u2013phenotype correlation in PRKN-associated Parkinson\u2019s disease"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0739-3313","authenticated-orcid":false,"given":"Poornima 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H.M. is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia and Amylyx; lecture fees\/honoraria\u2014BMJ, Kyowa Kirin, Movement Disorders Society. Research Grants from Parkinson\u2019s UK, Cure Parkinson\u2019s Trust, PSP Association, Medical Research Council, Michael J Fox Foundation. H.W.M. is a co-applicant on a patent application related to C9ORF72\u2014Method for diagnosing a neurodegenerative disease (PCT\/GB2012\/052140). Z.G. Or received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Inceptions Sciences (now Ventus), Ono Therapeutics, Bial Biotech, Bial, Handl Therapeutics, UCB, Capsida, Denali Lighthouse, Guidepoint and Deerfield. E.R. was supported by Soci\u00e9t\u00e9 Fran\u00e7aise de M\u00e9decine esth\u00e9tique and Enjoysharing for his work on Parkinson disease. Jean-Christophe Corvol has served in advisory boards for Alzprotect, Bayer, Biogen, Denali, Ferrer, Idorsia, Prevail Therapeutic, Servier, Theranexus, UCB; and received grants from Sanofi. Kailash P. Bhatia has received grant support from Wellcome\/MRC, NIHR, Parkinson\u2019s UK and EU Horizon 2020. He receives royalties from the publication of the Oxford Specialist Handbook Parkinson\u2019s Disease and Other Movement Disorders (Oxford University Press, 2008), of Marsden\u2019s Book of Movement Disorders (Oxford University Press, 2012), and of Case Studies in Movement Disorders\u2014Common and uncommon presentations (Cambridge University Press, 2017). He has received honoraria\/personal compensation for participating as consultant\/scientific board member from Ipsen, Allergan, Merz and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals and from the American Academy of Neurology and the International Parkinson\u2019s Disease and Movement Disorders Society. H.H. is grateful for the essential support from patients and families and for grateful funding from The Wellcome Trust, The MRC, The MSA Trust, The National Institute for Health Research University College London Hospitals Biomedical Research Centre, The Michael J Fox Foundation (MJFF), BBSRC, The Fidelity Trust, Rosetrees Trust, Ataxia UK, Brain Research UK, Sparks GOSH Charity, Alzheimer\u2019s Research UK (ARUK) and CureDRPLA. D.N. has a research collaboration with Spark Therapeutics for which he receives research funding support. M.B. received honoraria from Ipsen Pharma. L.-L.M. has received research support grants from INSERM, JNLF, The L\u2019Oreal Foundation, the French Parkinson Association, Fondation of France, Paris Brain Institute BBT and Neurocatalyst calls; speech honoraria from CSL, Sanofi-Genzyme, Lundbeck, Teva; consultant for Accure therapeutics, Sanofi and received travel funding from the Movement Disorders Society, ANAINF, Merck, Merz, Medtronic, Teva and AbbVie, outside the submitted work. All other authors declare no financial or non-financial competing interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"72"}}