Type of publication:
Journal article
Author(s):
Fang Z.-H.; Tan M.M.X.; Schmaderer T.M.; Stafford E.J.; Pollard M.; Tilney R.; Hodgson M.; Wu L.; Labrum R.; Hehir J.; Polke J.; Lange L.M.; Schapira A.H.V.; Bhatia K.P.; Hartley L.; Nacorda A.; Gentilini I.; Wales E.; Amar K.; Tuck S.; Raw J.; Crouch R.; Walker R.; Hand A.; Strens L.; Sveinbjornsdottir S.; Webster G.; Williams S.; Schrag A.; Nath U.; Mann C.; D'Costa D.; Barnes C.; Jones E.; Slaght S.J.; Wiblin L.; Archibald N.; *Capps E.; Jones S.; Sophia R.; Vickers C.; Dean S.; Truscott R.; Sheridan R.; Brierley C.; Kunc M.; Funaki A.; Asad S.; Tai Y.; Chaudhuri R.; Guptha S.; Cosgrove J.; Misbahuddin A.; Padiachy D.; Paviour D.; Bandmann O.; Buccoliero R.; Wickremaratchi M.; Gregory R.; Molloy S.; Shaik S.; Arianayagam S.; Saifee T.; Wakeman E.; Towns C.; Jasaityte S.; Jarman P.R.; Singleton A.B.; Blauwendraat C.; Klein C.; Houlden H.; Wood N.W.; Morris H.R.; Real R.
Citation:
npj Parkinson's Disease. 10(1) (no pagination), 2024. Article Number: 188. Date of Publication: December 2024.
Abstract:
The Parkinson's Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson's disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset <=45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset <=35 years. We identified pathogenic variants in LRRK2 in 4.2% of families, and biallelic pathogenic variants in PRKN in 3.6% of families. We also identified two families with SNCA duplications and three families with a pathogenic repeat expansion in ATXN2, as well as single families with pathogenic variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk GBA1 variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.
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