Rare variants in PLXNA4 and Parkinson's disease.
Approximately 20% of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.
Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität, München, Munich, Germany ; Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.
Eva C
EC
Schulte
Immanuel
I
Stahl
Darina
D
Czamara
Daniel C
DC
Ellwanger
Sebastian
S
Eck
Elisabeth
E
Graf
Brit
B
Mollenhauer
Alexander
A
Zimprich
Peter
P
Lichtner
Dietrich
D
Haubenberger
Walter
W
Pirker
Thomas
T
Brücke
Benjamin
B
Bereznai
Maria J
MJ
Molnar
Annette
A
Peters
Christian
C
Gieger
Bertram
B
Müller-Myhsok
Claudia
C
Trenkwalder
Juliane
J
Winkelmann
D016022:Case-Control Studies; D005190:Family; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000235:genetics*; D019683:Penetrance; D011956:Receptors, Cell Surface / Q000235:genetics*
C524474:Plxna4 protein, human; D011956:Receptors, Cell Surface