Phase analysis identifies compound heterozygous deletions of the <i>PARK2</i> gene in patients with early‐onset Parkinson disease

Kim, S Y; Seong, Moon Woo; Jeon, Beom S.; Ko, Hyojin; Kim, J Y; Park, Sung Sup

doi:10.1111/j.1399-0004.2011.01693.x

Cited by 26 publications

(23 citation statements)

References 21 publications

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“…Gene studies of parkin, PINK-1, DJ-1, SNCA, LRRK2 G2019S, SCA2, and SCA17 mutations were conducted as described elsewhere [27][28][29][30][31]. Parkin mutations were identified by both sequence analysis and gene dosage analysis [multiplex ligation-dependent probe amplification P051/P052 kit (MRC-Holland, Amsterdam, The Netherlands)].…”

Section: Molecular Genetic Analysismentioning

confidence: 99%

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Phenotype analysis in patients with early onset Parkinson’s disease with and without parkin mutations

Kim

Lee

et al. 2011

J Neurol

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The data regarding whether parkin genotype attributes phenotypic variation are conflicting. Since the incidence of parkin mutations is very low in patients with an age at onset (AAO) of >40 years, previous studies have unfairly compared phenotypes of two early onset Parkinson's disease (EOPD) groups with different AAOs. Thus, we compared the clinical features between patients with and without parkin mutations in EOPD with an AAO of ≤40 years. Of the 124 patients with EOPD with an AAO of ≤40 years who were recruited and screened for parkin mutations, 84 completed assessments for comparison of the phenotype according to parkin genotype. Fourteen of the 84 subjects carried two parkin mutations; 6, a single mutation; and 64, no mutations. Patients with two mutations had significantly younger AAOs, longer duration of PD, and more common family history than patients without parkin mutations. Otherwise, motor and nonmotor symptoms did not differ between them. Subgroup analysis of EOPD with an AAO of ≤35 years revealed similar results. Phenotype of EOPD may depend on early AAOs rather than presence of parkin mutations.

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Section: Molecular Genetic Analysismentioning

confidence: 99%

“…Parkin mutations were identified by both sequence analysis and gene dosage analysis [multiplex ligation-dependent probe amplification P051/P052 kit (MRC-Holland, Amsterdam, The Netherlands)]. Detailed methods were previously described [27].…”

Section: Molecular Genetic Analysismentioning

confidence: 99%

Phenotype analysis in patients with early onset Parkinson’s disease with and without parkin mutations

Kim

Lee

et al. 2011

J Neurol

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“…While compound heterozygous CNVs in PRKN have been previously described in EOPD (Kim et al., 2012), this case is illustrative for several reasons. First, this case demonstrates the utility of CMA in the detection of copy number variation contributing to Parkinson disease and Parkinsonian syndromes.…”

Section: Discussionmentioning

confidence: 98%

Phase determination using chromosomal microarray and fluorescence in situ hybridization in a patient with early onset Parkinson disease and two deletions in PRKN

Williams

Barrett

Dhamija

et al. 2018

Molec Gen & Gen Med

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BackgroundMutations in the parkin gene (PRKN) are the most commonly identified genetic factors in early onset Parkinson disease (EOPD), with biallelic mutations, resulting in a clinical phenotype. However, normal variation is also common in PRKN, particularly in the form of copy number variation (CNV), challenging interpretation of genetic testing results. Here we report a case of a 29‐year‐old male with EOPD and two deletions in PRKN detected by chromosomal microarray (CMA).MethodsThe proband was clinically examined by a neurologist for postural instability with frequent falls, bradykinesia, gait freezing with festination, and hypophonia. Chromosomal microarray analysis (CMA) was performed on the proband and his parents using the Affymetrix CytoScan HD microarray. Subsequent fluorescence in situ hybridization (FISH) was performed on the proband and both parents.ResultsChromosomal microarray detected the presence of two deletions of PRKN in the proband. Parental CMA analysis was performed to determine the clinical significance of this finding, as well as to demonstrate phase of these deletions. Parental CMA revealed that one deletion was paternally inherited and one deletion was de novo. A custom FISH approach was then successfully used to phase the deletions.ConclusionChromosomal microarray and fluorescence in situ hybridization analysis of this trio identified two deletions in PRKN occurring in trans, providing a genetic etiology for the clinical diagnosis of EOPD. The determination of inheritance and phase of the deletions was critical to the proper interpretation of these results. These findings highlight the utility of CMA in the detection of clinically relevant CNVs in cases of EOPD, and also serve to emphasize the importance of follow‐up FISH and parental testing.

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“…These data suggest the existence of five additional exons that, however, have never been considered for dosage screening. CNV rearrangements involving PARK2 exons accounts for 50-60% of all pathogenic anomalies, rendering gene-dosage assays essential in Parkin mutational screening [81]. However, the hot-spot nature of this gene makes its quantitative analysis a particular challenge, and several issues need to be pointed out in this regard.…”

Section: Park2mentioning

confidence: 99%

“…Kim et al [81] have showed that phase determination is a prerequisite for PARK2 molecular diagnosis: by phase determination, several patients with apparent contiguous multi-exon deletions were re-diagnosed as compound heterozygotes. Simple gene-dosage assays seem to be not sufficient to determine the phase of rearrangements, and therefore, the true incidence of molecularly confirmed Parkin-type early-onset PD may be underestimated.…”

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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Phase analysis identifies compound heterozygous deletions of the PARK2 gene in patients with early‐onset Parkinson disease

Cited by 26 publications

References 21 publications

Phenotype analysis in patients with early onset Parkinson’s disease with and without parkin mutations

Phenotype analysis in patients with early onset Parkinson’s disease with and without parkin mutations

Phase determination using chromosomal microarray and fluorescence in situ hybridization in a patient with early onset Parkinson disease and two deletions in PRKN

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

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