Association of Dual-Task Gait Cost and White Matter Hyperintensity Burden Poststroke: Results From the ONDRI.

Background: Acute change in gait speed while performing a mental task [dual-task gait cost (DTC)], and hyperintensity magnetic resonance imaging signals in white matter are both important disability predictors in older individuals with history of stroke (poststroke). It is still unclear, however, whether DTC is associated with overall hyperintensity volume from specific major brain regions in poststroke.

Methods: This is a cohort study with a total of 123 older (69 ± 7 years of age) participants with history of stroke were included from the Ontario Neurodegenerative Disease Research Initiative.

Axial Impairment Following Deep Brain Stimulation in Parkinson's Disease: A Surgicogenomic Approach.

Background: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed "surgicogenomics".

Objective: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson's disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome.

The Intersection between COVID-19, the Gene Family of ACE2 and Alzheimer's Disease.

We reviewed factors that might influence COVID-19 outcomes (eg, neurological symptoms), including the link to Alzheimer's disease. Since the virus triggers COVID-19 infection through binding to ACE2, we focused on the gene family, including . Both ACE2 and ACE are involved in the renin-angiotensin system (RAS).

Interplay between probe design and test performance: overlap between genomic regions of interest, capture regions and high quality reference calls influence performance of WES-based assays.

Whole exome sequencing (WES)-based assays undergo rigorous validation before being implemented in diagnostic laboratories. This validation process generates experimental evidence that allows laboratories to predict the performance of the intended assay. The NA12878 Genome in a Bottle (GIAB) HapMap reference sample is commonly used for validation in diagnostic laboratories.

ALU transposition induces familial hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant-negative fashion. However loss-of-function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3, suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis.

Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative.

Background/objective: Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer's disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes.

Adopting High-Resolution Allele Frequencies Substantially Expedites Variant Interpretation in Genetic Diagnostic Laboratories.

A cohort of 1242 individuals tested in a clinical diagnostic laboratory was used to test whether the filtering allele frequencies (FAFs)-based framework, recently recommended for MHY7-associated cardiomyopathy, is extendable to 45 cardiomyopathy genes. Statistical analysis revealed a threshold of 0.00164% for the extreme outlier allele frequencies (AFs), based on the Genome Aggregation Database (exome fraction) total AFs of 138 unique pathogenic and likely pathogenic variants; 135 of them (97.

Genetic Diagnostic Testing for Inherited Cardiomyopathies: Considerations for Offering Multi-Gene Tests in a Health Care Setting.

Inherited cardiomyopathies (ICs) are a major cause of heart disease. Given their marked clinical and genetic heterogeneity, the content and clinical utility of IC multi-gene panels has been the topic of continuous debate. Our genetics diagnostic laboratory has been providing clinical diagnostic testing for ICs since 2012.

Leveraging the power of new molecular technologies in the clinical setting requires unprecedented awareness of limitations and drawbacks: experience of one diagnostic laboratory.

Background: Advances in molecular technologies and in-silico variant prediction tools offer wide-ranging opportunities in diagnostic settings, yet they also present with significant limitations.

Objective: Here, we contextualise the limitations of next-generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA) and in-silico prediction tools routinely used by diagnostic laboratories by reviewing specific experiences from our diagnostic laboratory.

Methods: We investigated discordant annotations and/or incorrect variant 'callings' in exons of 56 genes constituting our cardiomyopathy and connective tissue disorder NGS panels.

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease.

Next-generation sequencing (NGS) is quickly revolutionizing how research into the genetic determinants of constitutional disease is performed. The technique is highly efficient with millions of sequencing reads being produced in a short time span and at relatively low cost. Specifically, targeted NGS is able to focus investigations to genomic regions of particular interest based on the disease of study.

An APOE-independent cis-eSNP on chromosome 19q13.32 influences tau levels and late-onset Alzheimer's disease risk.

Although multiple susceptibility loci for late-onset Alzheimer's disease (LOAD) have been identified, a large portion of the genetic risk for this disease remains unexplained. LOAD risk may be associated with single-nucleotide polymorphisms responsible for changes in gene expression (eSNPs). To detect eSNPs associated with LOAD, we integrated data from LOAD genome-wide association studies and expression quantitative trait loci using Sherlock (a Bayesian statistical method).

Reinterpretation of sequence variants: one diagnostic laboratory's experience, and the need for standard guidelines.

PurposeThe advent of next-generation sequencing resulted in substantial increases in the number of variants detected, interpreted, and reported by molecular genetics diagnostic laboratories. Recent publications have provided standards for the interpretation of sequence variants, but there are currently no standards regarding reinterpretation of these variants. Recognizing that significant changes in variant classification may occur over time, many genetics diagnostic laboratories have independently developed practices for variant reinterpretation.

Characterizing familial corticobasal syndrome due to Alzheimer's disease pathology and PSEN1 mutations.

Introduction: Corticobasal syndrome (CBS) resulting from genetic Alzheimer's disease (AD) has been described only once. Whether familial CBS-AD is a distinct clinical entity with its own imaging signature remains unknown.

Methods: Four individuals with CBS from two families underwent detailed assessment.

The ONDRISeq panel: custom-designed next-generation sequencing of genes related to neurodegeneration.

The Ontario Neurodegenerative Disease Research Initiative (ONDRI) is a multimodal, multi-year, prospective observational cohort study to characterise five diseases: (1) Alzheimer's disease (AD) or amnestic single or multidomain mild cognitive impairment (aMCI) (AD/MCI); (2) amyotrophic lateral sclerosis (ALS); (3) frontotemporal dementia (FTD); (4) Parkinson's disease (PD); and (5) vascular cognitive impairment (VCI). The ONDRI Genomics subgroup is investigating the genetic basis of neurodegeneration. We have developed a custom next-generation-sequencing-based panel, ONDRISeq that targets 80 genes known to be associated with neurodegeneration.

Genetic Variations in ABCA7 Can Increase Secreted Levels of Amyloid-β40 and Amyloid-β42 Peptides and ABCA7 Transcription in Cell Culture Models.

Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.

Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set.

Genome wide association studies have identified an association between Alzheimer's disease (AD) and common polymorphisms in the MS4A and TREM loci (each containing a cluster of homologous genes) and should be thoroughly investigated for the presence of potentially functional variations. We conducted a mutation analysis by next generation sequencing of 15 genes within the MS4A and TREM gene clusters; and catalogued rare coding variants detected in a North American data set of 210 cases and 233 controls. Investigation of the 5 homologues genes in the TREM locus revealed potentially damaging rare variants in TREM2, TREML1, TREML2, and TREML4.

Novel GRN Mutations in Patients with Corticobasal Syndrome.

Loss-of-function GRN mutations lead to GRN haploinsufficiency and consequently neurodegeneration with significant heterogeneity in clinical presentation of various syndromes. The aim of this study was to investigate the genetics and clinical features of patients with GRN-related frontotemporal lobar degeneration (FTLD) syndromes. We performed mutation analysis of GRN in 45 unrelated Canadian patients with a broad spectrum of FTLD-like syndromes (mean age at onset of 64.

Mutation analysis of CHCHD2 in Canadian patients with familial Parkinson's disease.

Recently, several CHCHD2 mutations were reported to be associated with autosomal dominant Parkinson's disease (PD) in a Japanese population. However, an association between CHCHD2 and PD was not observed in 2 Caucasian data sets. The present study searched for CHCHD2 coding variants in Canadian PD patients.

MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis.

Tar DNA-binding protein 43 (TDP-43) is an RNA-binding protein normally localized to the nucleus of cells, where it elicits functions related to RNA metabolism such as transcriptional regulation and alternative splicing. In amyotrophic lateral sclerosis, TDP-43 is mislocalized from the nucleus to the cytoplasm of diseased motor neurons, forming ubiquitinated inclusions. Although mutations in the gene encoding TDP-43, TARDBP, are found in amyotrophic lateral sclerosis, these are rare.

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.

Importance: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.

Objective: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.

Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci.

Objective: To detect rare coding variants underlying loci detected by genome-wide association studies (GWAS) of late onset Alzheimer disease (LOAD).

Methods: We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry-matched controls.

Inbreeding among Caribbean Hispanics from the Dominican Republic and its effects on risk of Alzheimer disease.

Background: Inbreeding can be associated with a modification of disease risk due to excess homozygosity of recessive alleles affecting a wide range of phenotypes. We estimated the inbreeding coefficient in Caribbean Hispanics and examined its effects on risk of late-onset Alzheimer disease.

Methods: The inbreeding coefficient was calculated in 3,392 subjects (1,451 late-onset Alzheimer disease patients and 1,941 age-matched healthy controls) of Caribbean Hispanic ancestry using 177,997 nearly independent single-nucleotide polymorphisms from genome-wide array.