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

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

doi:10.3389/fneur.2020.00682

Abstract

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.

Highlights

Heterozygous sequence variants of leucine-rich repeat kinase 2 (LRRK2) or vacuolar protein sorting 35 (VPS35), and mutations or genomic rearrangements in SNCA cause monogenic Parkinson’s disease (PD) with autosomal dominant (AD) inheritance [reviewed in [1]]
An analysis of PD cases according to age at onset (≤50 years vs. >50 years) showed that LRRK2 mutations were more frequent among late-onset PD cases (61/636, 9.6%; 95% confidence intervals (CIs) [7.4–12.2] vs. 71/1063, 6.7%; 95% CI [5.3–8.4], Fisher’s exact test: odds ratios (ORs) 1.5, 95% CI [1.0–2.1], p = 0.03; Table 2)
We considered patients with missing age at onset (AAO) data examined at an age ≤50 years (n = 26) to have early-onset PD

Summary

Introduction

Heterozygous sequence variants of LRRK2 or VPS35, and mutations or genomic rearrangements in SNCA cause monogenic Parkinson’s disease (PD) with autosomal dominant (AD) inheritance [reviewed in [1]]. SNCA mutations are the second most common cause of autosomal dominant inherited PD; genomic duplications have been detected in ∼1–2% of families with AD PD. VPS35 was the first PD-causing gene to be identified by nextgeneration sequencing (NGS) in large multi-incident families [5, 6]. Subsequent studies in multiple ethnic groups, including a large multi-center study, indicated that Asp620Asn was the only pathogenic variant, with a relative frequency ranging from 0.1 to 1% in familial PD, depending on population background [7]. As the phenotype of AD PD closely resembles that of idiopathic PD, we assumed that rare variants of genes causing AD PD might contribute to the etiology of isolated PD in the French population

Methods

Discussion

Conclusion