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Rare variants in PLXNA4 and Parkinson's disease.

Schulte EC, Stahl I, Czamara D, Ellwanger DC, Eck S, Graf E, Mollenhauer B, Zimprich A, Lichtner P, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Peters A, Gieger C, Müller-Myhsok B, Trenkwalder C, Winkelmann J - PLoS ONE (2013)

Bottom Line: Yet, a large portion of causal and disease-modifying variants is still unknown.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.

View Article: PubMed Central - PubMed

Affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität, München, Munich, Germany ; Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.

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.

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Pedigree and Linkage Analysis.(A) Pedigree of family used for exome sequencing. Open symbols indicate unaffected family members, affected individuals are denoted by closed symbols. An arrow denotes the individuals whose exomes were sequenced. Sex was obscured and birth order was altered to protect privacy. A diagonal line indicates a deceased individual. (B) 25 genomic regions on 12 chromosomes with logarithm of the odds (LOD) score≥0.5 were identified by linkage analysis. Green boxes represent genomic regions with LOD≥0.5, yellow stars represent the location of the four candidate genes remaining after frequency assessment (GOLGA4-chr3, PLXNA4-chr7, OGN-chr9, CPNE1-chr20). PLXNA4 on chromosome 7 represents the only of the four genes overlapping a genomic region with LOD≥0.5.
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pone-0079145-g001: Pedigree and Linkage Analysis.(A) Pedigree of family used for exome sequencing. Open symbols indicate unaffected family members, affected individuals are denoted by closed symbols. An arrow denotes the individuals whose exomes were sequenced. Sex was obscured and birth order was altered to protect privacy. A diagonal line indicates a deceased individual. (B) 25 genomic regions on 12 chromosomes with logarithm of the odds (LOD) score≥0.5 were identified by linkage analysis. Green boxes represent genomic regions with LOD≥0.5, yellow stars represent the location of the four candidate genes remaining after frequency assessment (GOLGA4-chr3, PLXNA4-chr7, OGN-chr9, CPNE1-chr20). PLXNA4 on chromosome 7 represents the only of the four genes overlapping a genomic region with LOD≥0.5.

Mentions: 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). Clinical assessment revealed tremor-dominant, levodopa-responsive parkinsonism with an age of onset at 60 and 67 years of age in the two affected individuals examined (Table S1 in File S1). Both individuals also reported subjective cognitive impairment. Restless legs syndrome was present in IV:11 as well as one of her children. Transcranial ultrasound showed bilateral hyperechogenicity of the substantia nigra in IV:18 but was not performed in IV:11. MRI was in line with a diagnosis of PD in both. The affected parent (III:7) and aunt (III:5) of IV:11 were deceased before initiation of the study, so that no detailed phenotype information is available. Moreover, another aunt (III:2) on the same side of the family was reported to have suffered from an unclassified form of dementia.


Rare variants in PLXNA4 and Parkinson's disease.

Schulte EC, Stahl I, Czamara D, Ellwanger DC, Eck S, Graf E, Mollenhauer B, Zimprich A, Lichtner P, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Peters A, Gieger C, Müller-Myhsok B, Trenkwalder C, Winkelmann J - PLoS ONE (2013)

Pedigree and Linkage Analysis.(A) Pedigree of family used for exome sequencing. Open symbols indicate unaffected family members, affected individuals are denoted by closed symbols. An arrow denotes the individuals whose exomes were sequenced. Sex was obscured and birth order was altered to protect privacy. A diagonal line indicates a deceased individual. (B) 25 genomic regions on 12 chromosomes with logarithm of the odds (LOD) score≥0.5 were identified by linkage analysis. Green boxes represent genomic regions with LOD≥0.5, yellow stars represent the location of the four candidate genes remaining after frequency assessment (GOLGA4-chr3, PLXNA4-chr7, OGN-chr9, CPNE1-chr20). PLXNA4 on chromosome 7 represents the only of the four genes overlapping a genomic region with LOD≥0.5.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3823607&req=5

pone-0079145-g001: Pedigree and Linkage Analysis.(A) Pedigree of family used for exome sequencing. Open symbols indicate unaffected family members, affected individuals are denoted by closed symbols. An arrow denotes the individuals whose exomes were sequenced. Sex was obscured and birth order was altered to protect privacy. A diagonal line indicates a deceased individual. (B) 25 genomic regions on 12 chromosomes with logarithm of the odds (LOD) score≥0.5 were identified by linkage analysis. Green boxes represent genomic regions with LOD≥0.5, yellow stars represent the location of the four candidate genes remaining after frequency assessment (GOLGA4-chr3, PLXNA4-chr7, OGN-chr9, CPNE1-chr20). PLXNA4 on chromosome 7 represents the only of the four genes overlapping a genomic region with LOD≥0.5.
Mentions: 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). Clinical assessment revealed tremor-dominant, levodopa-responsive parkinsonism with an age of onset at 60 and 67 years of age in the two affected individuals examined (Table S1 in File S1). Both individuals also reported subjective cognitive impairment. Restless legs syndrome was present in IV:11 as well as one of her children. Transcranial ultrasound showed bilateral hyperechogenicity of the substantia nigra in IV:18 but was not performed in IV:11. MRI was in line with a diagnosis of PD in both. The affected parent (III:7) and aunt (III:5) of IV:11 were deceased before initiation of the study, so that no detailed phenotype information is available. Moreover, another aunt (III:2) on the same side of the family was reported to have suffered from an unclassified form of dementia.

Bottom Line: Yet, a large portion of causal and disease-modifying variants is still unknown.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.

View Article: PubMed Central - PubMed

Affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität, München, Munich, Germany ; Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.

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.

Show MeSH
Related in: MedlinePlus