Abstract
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.
Highlights
Characterized by resting-tremor, bradykinesia, rigidity, and postural instability, Parkinson’s disease (PD) is one of the most prominent neurodegenerative disorders
Pedigree and Clinical Phenotype We describe a five-generation family from Central Germany in which four members were affected by PD and the pattern of inheritance seems to be autosomal dominant with reduced penetrance (Figure 1)
Whole-exome approach, we identified a variant in PLXNA4 (p.Ser657Asn) as a candidate for a potentially causal variant in familial PD
Summary
Characterized by resting-tremor, bradykinesia, rigidity, and postural instability, Parkinson’s disease (PD) is one of the most prominent neurodegenerative disorders. Up to 20% of PD cases are believed to be familial [1,2], far, variants in only a few genes have been unequivocally shown to underlie familial PD These include PARK2, PINK1, PARK7, SNCA, and LRRK2 [3,4,5,6,7,8]. While all of these genes were identified by classical linkage analysis in large, multi-generation families, recently, next-generation sequencing has enabled the identification of disease-causing variants in smaller families and with an onset later in life without the need of genotypic information from more than one generation of affected individuals. We describe exome sequencing of a German family with autosomal dominant late-onset PD in an attempt to pinpoint the disease-causing genetic variant
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
