A multicenter study of genetic testing for Parkinson’s disease in the clinical setting

Kovanda, Anja; Rački, Valentino; Bergant, Gaber; Georgiev, Dejan; Flisar, Dušan; Papić, Eliša; Branković, Miloš; Janković, Milena; Svetel, Marina; Teran, Nataša; Maver, Aleš; Kostić, Vladimir; Novaković, Ivana; Pirtošek, Zvezdan; Rakuša, Martin; Vuletić, Vladimira; Peterlin, Borut

doi:10.1038/s41531-022-00408-6

Cited by 13 publications

(8 citation statements)

References 27 publications

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“…In most populations, there is still a lack of genetic studies that include patients in all possible onset types of PD and often focus on patients with a positive family history of PD or an early onset of the disease. A study has been published involving several patients from this cohort as part of a larger group of patients with early and familial onset from Croatia, Slovenia, and Serbia, where GBA was the most common causative genetic factor for the development of Parkinson's disease, with a higher percentage of patients with causative variants, possibly because sporadic patients were not included [17]. Similar results are observed in neighboring Italy, in an isolated population in Sardinia, where GBA and PRKN variants were the most common but in a smaller percentage than in our study (4.4%) [33].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, information on the expected diagnostic yield of genetic testing is important for informing clinical decisions. To address this issue, we recently published a collaborative next-generation sequencing (NGS) genetic study in EO and FO PD patients from the Serbian, Slovenian, and Croatian populations, the first South Slavic population study [17].…”

Section: Introductionmentioning

confidence: 99%

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GiOPARK Project: The Genetic Study of Parkinson’s Disease in the Croatian Population

Rački,

Bergant,

Papić

et al. 2024

Genes

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Parkinson’s disease is a neurological disorder that affects motor function, autonomic functions, and cognitive abilities. It is likely that both genetic and environmental factors, along with age, contribute to the cause. However, there is no comprehensive guideline for genetic testing for Parkinson’s disease, and more research is needed to understand genetic variations in different populations. There has been no research on the genetic background of Parkinson’s disease in Croatia so far. Therefore, with the GiOPARK project, we aimed to investigate the genetic variants responsible for Parkinson’s disease in 153 Croatian patients with early onset, familial onset, and sporadic late-onset using whole-exome sequencing, along with multiplex ligation-dependent probe amplification and Sanger sequencing in select patients. We found causative variants in 7.84% of the patients, with GBA being the most common gene (4.58%), followed by PRKN (1.96%), ITM2B (0.65%), and MAPT (0.65%). Moreover, variants of uncertain significance were identified in 26.14% of the patients. The causative variants were found in all three subgroups, indicating that genetic factors play a role in all the analyzed Parkinson’s disease subtypes. This study emphasizes the need for more inclusive research and improved guidelines to better understand the genetic basis of Parkinson’s disease and facilitate more effective clinical management.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GiOPARK Project: The Genetic Study of Parkinson’s Disease in the Croatian Population

Rački,

Bergant,

Papić

et al. 2024

Genes

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“…NGS requires significant investment (sequencers and computer servers), needs bioinformaticians and its analysis time is much longer. Other studies used different NGS methods in PD [21, 26] or early‐onset PD [22, 27]. All pathogenic variants (excluding GBA variants that are risk factors for PD) described in Illés et al [21] and Kovanda et al [26] could be observed using MLPA ± Sanger sequencing to look for a second mutation.…”

Section: Discussionmentioning

confidence: 99%

Indication for molecular testing by multiplex ligation‐dependent probe amplification in parkinsonism

Mutez

Swiderski²,

Devos

et al. 2023

Euro J of Neurology

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Background and purpose:The monogenic forms of Parkinson's disease represent <10% of familial cases and a still lower frequency of sporadic cases. However, guidelines to orient genetic testing are lacking. The aim was to establish the interest of multiplex ligationdependent probe amplification (MLPA) as a primary screening test and to propose clinical criteria to guide genetic diagnostic tests for patients with suspected Mendelian Parkinson's disease.Methods: In all, 567 patients with parkinsonism from 547 unrelated families were recruited and two MLPAs were performed for each. All pathogenic G2019S variants in the LRRK2 gene were confirmed by Sanger sequencing and the PRKN gene was screened for a second mutation in the cases of one heterozygous structural variant in the PRKN gene. Results:The performance of MLPA was 51/567 (9%) for the entire cohort and included 27 (4.8%) LRRK2 G2019S mutations, 19 (3.4%) PRKN mutations and five (0.9%) SNCA locus duplications. The variables significantly associated with a positive test in the total cohort were North African ancestry (p < 0.0001), female sex (p = 0.004) and younger age at onset (p < 0.0008). Conclusions:Retrospective analysis allowed us to refine our indication criteria: (i) North African ancestry, (ii) an age at onset <40 years or (iii) a familial history of parkinsonism with at least one affected first-degree relative. Our study highlights the interest of MLPA

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“…Between January 2014 and July 2019, 27 individuals underwent clinical exome sequencing and between July 2019 and December 2022, 93 individuals underwent exome sequencing. Sequencing and data analysis were performed at our institute as previously described [35][36][37]. For clinical and exome sequencing, the median minimum exome coverage was 60x, with more than 95% of the targets covered with at least 10x sequencing depth.…”

Section: Sequencing and Bioinformatics Analysismentioning

confidence: 99%

A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study

Vodnjov,

Toplišek,

Maver

et al. 2023

PLoS ONE

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Founder variants in sarcomere protein genes account for a significant proportion of disease-causing variants in patients with hypertrophic cardiomyopathy (HCM). However, information on founder variants in non-sarcomeric protein genes, such as FHOD3, which have only recently been associated with HCM, remains scarce. In this study, we conducted a retrospective analysis of exome sequencing data of 134 probands with HCM for recurrent pathogenic variants. We discovered a novel likely pathogenic variant c.1646+2T>C in FHOD3 in heterozygous state in eight probands with HCM and confirmed its presence in seven additional relatives. Individuals with this variant had a wide range of ages at onset of the disease (4–63 years). No adverse cardiac events were observed. Haplotype analysis revealed that the individuals with this variant shared a genomic region of approximately 5 Mbp surrounding the variant, confirming the founder effect of the variant. FHOD3 c.1646+2T>C is estimated to have arisen 58 generations ago (95% CI: 45–81) in a common ancestor living on the Balkans. A founder FHOD3 c.1646+2T>C variant is the second most common genetic variant in our cohort of patients with HCM, occurring in 16% of probands with a known genetic cause of HCM, which represents a substantially higher proportion than the currently estimated 0.5–2% for causal FHOD3 variants. Our study broadens the understanding of the genetic causes of HCM and may improve the diagnosis of this condition, particularly in patients from the Balkans.

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A multicenter study of genetic testing for Parkinson’s disease in the clinical setting

Cited by 13 publications

References 27 publications

GiOPARK Project: The Genetic Study of Parkinson’s Disease in the Croatian Population

GiOPARK Project: The Genetic Study of Parkinson’s Disease in the Croatian Population

Indication for molecular testing by multiplex ligation‐dependent probe amplification in parkinsonism

A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study

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