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

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

JOURNAL=Frontiers in Neurology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2020.00682

DOI=10.3389/fneur.2020.00682

ISSN=1664-2295

ABSTRACT=<p><italic>LRRK2, SNCA</italic>, and <italic>VPS35</italic> are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of <italic>LRRK2, SNCA</italic>, and <italic>VPS35</italic> 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 <italic>LRRK2</italic> 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 <italic>LRRK2</italic> variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with <italic>SNCA</italic> point mutations or genomic rearrangements (1.1%), and three with the <italic>VPS35</italic> 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], <italic>p</italic> = 0.001). PD patients with <italic>LRRK2</italic> variants were more likely to have higher rates of late-onset PD (&gt;50 years; OR 1.5, 95% CI [1.0–2.1], <italic>p</italic> = 0.03), whereas those with <italic>SNCA</italic> mutations tended to have earlier age at onset disease (≤ 50 years, <italic>p</italic> = 0.06). The clinical features of <italic>LRRK2</italic> 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.</p>