Multi-centre evaluation of a comprehensive preimplantation genetic test through haplotyping-by-sequencing.

Study Question: Can reduced representation genome sequencing offer an alternative to single nucleotide polymorphism (SNP) arrays as a generic and genome-wide approach for comprehensive preimplantation genetic testing for monogenic disorders (PGT-M), aneuploidy (PGT-A) and structural rearrangements (PGT-SR) in human embryo biopsy samples?

Summary Answer: Reduced representation genome sequencing, with OnePGT, offers a generic, next-generation sequencing-based approach for automated haplotyping and copy-number assessment, both combined or independently, in human single blastomere and trophectoderm samples.

What Is Known Already: Genome-wide haplotyping strategies, such as karyomapping and haplarithmisis, have paved the way for comprehensive PGT, i.e.

Mutations in glucocerebrosidase are a major genetic risk factor for Parkinson's disease and increase susceptibility to dementia in a Flanders-Belgian cohort.

Objective: To investigate the frequency of glucocerebrosidase (GBA) mutations in a Flanders-Belgian Parkinson's disease (PD) patient cohort and to assess genotype-phenotype correlations.

Methods: We performed an in-depth sequencing of all coding exons of GBA in 266 clinically well-characterized PD patients and 536 healthy control individuals.

Results: We identified rare, heterozygous GBA mutations in 12 PD patients (4.

Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.

Objectives: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD).

Methods: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes.

Progress in unraveling the genetic etiology of Parkinson disease in a genomic era.

Parkinson disease (PD) and Parkinson-plus syndromes are genetically heterogeneous neurological diseases. Initial studies into the genetic causes of PD relied on classical molecular genetic approaches in well-documented case families. More recently, these approaches have been combined with exome sequencing and together have identified 15 causal genes.

Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease.

Objectives: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort.

Methods: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia.

Results: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.

Alpha-synuclein repeat variants and survival in Parkinson's disease.

Objectives: To determine whether α-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD).

Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death.

Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

Background: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease.

Methods: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries.

A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies.

Importance: While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.

Objective: To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers.

Non-motor symptoms in a Flanders-Belgian population of 215 Parkinson's disease patients as assessed by the Non-Motor Symptoms Questionnaire.

Background: Non-motor symptoms (NMS) in Parkinson's disease (PD) are frequent, increase the patients' disability and have an important negative impact on their quality of life.

Methods: We used a Dutch translation of the Non-Motor Symptoms Questionnaire (NMSQuest) to identify NMS in a population of 215 Belgian PD patients.

Results: A median number of 8 NMS was reported per patient.

Amyloid pathology influences aβ1-42 cerebrospinal fluid levels in dementia with lewy bodies.

A significant proportion of patients with dementia with Lewy bodies (DLB) show Alzheimer's disease (AD) pathology like senile plaques and neurofibrillary tangles. Biomarkers in cerebrospinal fluid (CSF), such as amyloid-β1-42 (Aβ1-42), total tau (T-tau), and hyperphosphorylated tau (P-tau181P), are linked to the different pathological hallmarks of AD. We set up a study to investigate the influence of AD co-pathology on CSF biomarker concentrations and profiles in autopsy-confirmed DLB.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

Background: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.

A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats.

We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.

Guanosine triphosphate cyclohydrolase 1 promoter deletion causes dopa-responsive dystonia.

Background: Autosomal dominant dopa-responsive dystonia (AD-DRD) is caused by a biochemical defect primarily resulting from guanosine triphosphate cyclohydrolase 1 gene (GCH1) mutations. Few families have been reported without mutations in GCH1.

Methods: Genome-wide linkage analysis and positional cloning to identify the genetic defect in a Belgian AD-DRD family was carried out.

Large-scale replication and heterogeneity in Parkinson disease genetic loci.

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.

Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study.

The genetics of dementia with Lewy bodies: what are we missing?

Dementia with Lewy bodies is a complex brain disorder and a key member of the Lewy body disease spectrum. Its genetic etiology is unclear, and information is scattered. However, the results of molecular genetic studies imply a genetic and mechanistic overlap with Alzheimer disease, Parkinson disease with dementia, and Parkinson disease.

Locus-specific mutation databases for neurodegenerative brain diseases.

The Alzheimer disease and frontotemporal dementia (AD&FTLD) and Parkinson disease (PD) Mutation Databases make available curated information of sequence variations in genes causing Mendelian forms of the most common neurodegenerative brain disease AD, frontotemporal lobar degeneration (FTLD), and PD. They are established resources for clinical geneticists, neurologists, and researchers in need of comprehensive, referenced genetic, epidemiologic, clinical, neuropathological, and/or cell biological information of specific gene mutations in these diseases. In addition, the aggregate analysis of all information available in the databases provides unique opportunities to extract mutation characteristics and genotype-phenotype correlations, which would be otherwise unnoticed and unexplored.

Contribution of VPS35 genetic variability to LBD in the Flanders-Belgian population.

VPS35 was recently identified as a novel autosomal dominant gene for Parkinson disease. In this study, we aimed to determine the contribution of simple and complex VPS35 variations to the genetic etiology of the spectrum of Lewy body disorders (LBD) in a Flanders-Belgian patient cohort (n = 677). We identified 3 novel missense variations in addition to 1 silent and 1 intronic variation predicted to activate a cryptic splice site, but no copy number variations.

DLB and PDD: a role for mutations in dementia and Parkinson disease genes?

Based on the substantial overlap in clinical and pathological characteristics of dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) with Alzheimer disease (AD) and Parkinson disease (PD) we hypothesized that these disorders might share underlying genetic factors. The contribution of both sequence and copy number variants (CNVs) in known AD and PD genes to the genetic etiology of DLB and PDD however is currently unclear. Therefore, we performed a gene-based mutation analysis of all major AD and PD genes in 99 DLB and 75 PDD patients, including familial and sporadic forms, from Flanders, Belgium.

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.

Background: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.

Parkinson disease: insights in clinical, genetic and pathological features of monogenic disease subtypes.

In the past 15 years, insights in clinical and genetic characteristics of Parkinson disease (PD) have increased substantially. Sequence or copy number variants in at least six genes (SNCA, LRRK2, PARK2, PINK1, DJ-1 and ATP13A2) have been identified to cause monogenic forms of PD. Routine clinical testing for mutations in these genes is feasible and available, but overlapping phenotypes in monogenic and sporadic PD complicate straightforward diagnostic screening.

Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease.

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium.

Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update.

To date, molecular genetic analyses have identified over 500 distinct DNA variants in five disease genes associated with familial Parkinson disease; alpha-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucine-rich repeat kinase 2 (LRRK2). These genetic variants include approximately 82% simple mutations and approximately 18% copy number variations. Some mutation subtypes are likely underestimated because only few studies reported extensive mutation analyses of all five genes, by both exonic sequencing and dosage analyses.

Comprehensive genetic and mutation analysis of familial dementia with Lewy bodies linked to 2q35-q36.

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.

A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease.

High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients).