Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population

Nuytemans, Karen; Meeus, Bram; Crosiers, David; Brouwers, Nathalie; Goossens, Dirk; Engelborghs, Sebastiaan; Pals, Philippe; Pickut, Barbara A.; Broeck, Marleen Van den; Corsmit, Ellen; Cras, Patrick; Deyn, Peter Paul De; Del-Favero, Jurgen; Broeckhoven, Christine Van; Theuns, Jessie

doi:10.1002/humu.21007

Cited by 62 publications

(58 citation statements)

References 61 publications

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“…Ultimately, we analyzed all known as well as predicted genes extensively but did not identify a disease-causing mutation which could explain the disease in family DR246. Since more complex dosage effects have been associated with other neurodegenerative brain diseases like AD (AβPP duplication [32]) and PD [33], we tested for a DLB-related CNV in DR246 by conducting array-CGH experiments. We designed a very high density CNV array with > 150.000 overlapping probes covering the entire 3.3 Mb linked region to enable the detection of possible CNVs as small as 100 bp.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Genetic and Mutation Analysis of Familial Dementia with Lewy Bodies Linked to 2q35-q36

Meeus

Nuytemans

Crosiers

et al. 2010

JAD

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Abstract. The second most frequent form of neurodegenerative dementia after Alzheimer's disease is dementia with Lewy bodies (DLB). Since informative DLB families are scarce, little is presently known about the molecular genetic etiology of DLB. We recently mapped the first locus for DLB on chromosome 2q35-q36 in a multiplex Belgian family, DR246, with autopsy-proven DLB pathology in a region of 9.2 Mb. Here, we describe the ascertainment of additional DR246 family members and significant finemapping of the DLB locus to 3.3 Mb based on informative meiotic recombinants. Extensive sequencing of the 42 positional candidate genes within the DLB region did not identify a simple pathogenic mutation that co-segregated with disease in family DR246. Also high resolution analysis of copy number variations in the DLB locus did not provide evidence for a complex mutation. In conclusion, we confirmed the DLB locus at 2q35-q36 as a genetic entity but candidate gene-based sequencing and copy number variation analysis did not identify the pathogenic mutation in family DR246. Other detection strategies will be needed to reveal the underlying mutation explaining the linkage of DLB to 2q35-q26. Possibly the disease mutation in this family acts through a more complex mechanism than generally envisaged for monogenic disorders. Nevertheless, identifying the first familial DLB gene is likely to contribute an entry point into the pathogenic cascades underlying DLB pathology.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Genetic and Mutation Analysis of Familial Dementia with Lewy Bodies Linked to 2q35-q36

Meeus

Nuytemans

Crosiers

et al. 2010

JAD

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“…Their clinical course was similar to typical sporadic PD without severe progression or cognitive decline. Other cases of sporadic PD carrying de novo SNCA duplication were later revealed by different detection assays [55][56][57][58][59].…”

Section: Sncamentioning

confidence: 99%

“…For this reason, more than 200 putative pathogenic mutations have been reported worldwide, affecting numerous ethnic populations [33,35,59,[64][65][66][67][68][69][70][71][72][73][74][75][76][77]. The PARK2 mutation spectrum includes homozygous or compound heterozygous missense and nonsense point mutations, as well as several exon rearrangements (both duplications and deletions) involving all 12 exons and the promoter region.…”

Section: Park2mentioning

confidence: 99%

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

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Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.

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“…Troiano et al reported one sporadic cases among 101 young onset PD cases from French (1/101=1%) (Troiano et al, 2008). Nuytemans et al reported one duplication patient with dementia among 219 sporadic PD cases from Belgium (Nuytemans et al, 2009). Sironi et al reported one duplication patient with dementia among 144 PD cases from Italy (1/144=0.7%) (Sironi et al, 2009).…”

Section: The Frequency Of Snca Multiplications In Pdmentioning

confidence: 99%