Frontiers in Neurology (Jul 2020)

Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

  • Suzanne Lesage,
  • Suzanne Lesage,
  • Suzanne Lesage,
  • Suzanne Lesage,
  • Marion Houot,
  • Marion Houot,
  • Graziella Mangone,
  • Graziella Mangone,
  • Graziella Mangone,
  • Graziella Mangone,
  • Graziella Mangone,
  • Christelle Tesson,
  • Christelle Tesson,
  • Christelle Tesson,
  • Christelle Tesson,
  • Hélène Bertrand,
  • Hélène Bertrand,
  • Hélène Bertrand,
  • Hélène Bertrand,
  • Sylvie Forlani,
  • Sylvie Forlani,
  • Sylvie Forlani,
  • Sylvie Forlani,
  • Mathieu Anheim,
  • Mathieu Anheim,
  • Mathieu Anheim,
  • Christine Brefel-Courbon,
  • Christine Brefel-Courbon,
  • Emmanuel Broussolle,
  • Emmanuel Broussolle,
  • Emmanuel Broussolle,
  • Stéphane Thobois,
  • Stéphane Thobois,
  • Stéphane Thobois,
  • Philippe Damier,
  • Franck Durif,
  • Emmanuel Roze,
  • Emmanuel Roze,
  • Emmanuel Roze,
  • Emmanuel Roze,
  • Emmanuel Roze,
  • François Tison,
  • David Grabli,
  • David Grabli,
  • David Grabli,
  • David Grabli,
  • David Grabli,
  • Fabienne Ory-Magne,
  • Fabienne Ory-Magne,
  • Bertrand Degos,
  • Bertrand Degos,
  • François Viallet,
  • François Viallet,
  • Florence Cormier-Dequaire,
  • Florence Cormier-Dequaire,
  • Florence Cormier-Dequaire,
  • Florence Cormier-Dequaire,
  • Florence Cormier-Dequaire,
  • Anne-Marie Ouvrard-Hernandez,
  • Marie Vidailhet,
  • Marie Vidailhet,
  • Marie Vidailhet,
  • Marie Vidailhet,
  • Marie Vidailhet,
  • Ebba Lohmann,
  • Andrew Singleton,
  • Jean-Christophe Corvol,
  • Jean-Christophe Corvol,
  • Jean-Christophe Corvol,
  • Jean-Christophe Corvol,
  • Jean-Christophe Corvol,
  • Alexis Brice,
  • Alexis Brice,
  • Alexis Brice,
  • Alexis Brice,
  • for the French Parkinson disease Genetics Study Group(PDG)

DOI
https://doi.org/10.3389/fneur.2020.00682
Journal volume & issue
Vol. 11

Abstract

Read online

LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2–2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0–2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤ 50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.

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