Transcriptomics of Human Brain Tissue in Parkinson's Disease: a Comparison of Bulk and Single-cell RNA Sequencing.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease leading to motor dysfunction and, in some cases, dementia. Transcriptome analysis is one promising approach for characterizing PD and other neurodegenerative disorders by informing how specific disease events influence gene expression and contribute to pathogenesis. With the emergence of single-cell and single-nucleus RNA sequencing (scnRNA-seq) technologies, the transcriptional landscape of neurodegenerative diseases can now be described at the cellular level. As the application of scnRNA-seq is becoming routine, it calls to question how results at a single-cell resolution compare to those obtained from RNA sequencing of whole tissues (bulk RNA-seq), whether the findings are compatible, and how the assays are complimentary for unraveling the elusive transcriptional changes that drive neurodegenerative disease. Herein, we review the studies that have leveraged RNA-seq technologies to investigate PD. Through the integration of bulk and scnRNA-seq findings from human, post-mortem brain tissue, we use the PD literature as a case study to evaluate the compatibility of the results generated from each assay and demonstrate the complementarity of the sequencing technologies. Finally, through the lens of the PD transcriptomic literature, we evaluate the current feasibility of bulk and scnRNA-seq technologies to illustrate the necessity of both technologies for achieving a comprehensive insight into the mechanism by which gene expression promotes neurodegenerative disease. We conclude that the continued application of both assays will provide the greatest insight into neurodegenerative disease pathology, providing both cell-specific and whole-tissue level information.

Identification of gene fusions associated with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Genetics is an important risk factor for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Recent findings demonstrate that in addition to specific genetic mutations, structural variants caused by genetic instability can also play a causative role in ALS. Genomic instability can lead to deletions, duplications, insertions, inversions, and translocations in the genome, and these changes can sometimes lead to fusion of distinct genes into a single transcript. Gene fusion events have been studied extensively in cancer; however, they have not been thoroughly investigated in ALS. The aim of this study was to determine whether gene fusions are present in ALS. METHODS: Gene fusions were identified using STAR Fusion v1.10.0 software in bulk RNA-Seq data from human postmortem samples from publicly available data sets from Target ALS and the New York Genome Center ALS Consortium. RESULTS: We report the presence of gene fusion events in several brain regions as well as in spinal cord samples in ALS. Although most gene fusions were intra-chromosomal events between neighboring genes and present in both ALS and control samples, there was a significantly greater number of unique gene fusions in ALS compared to controls. Lastly, we identified specific gene fusions with a significant burden in ALS, that were absent from both control samples and known cancer gene fusion databases. DISCUSSION: Collectively, our findings reveal an enrichment of gene fusions in ALS and suggest that these events may be an additional genetic cause linked to ALS pathogenesis.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes.

Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants, particularly missense variants, many of which are of unknown clinical significance. Here, we leverage the sequencing efforts of the ALS Knowledge Portal (3864 individuals with ALS and 7839 controls) and Project MinE ALS Sequencing Consortium (4366 individuals with ALS and 1832 controls) to perform proteomic and transcriptomic characterization of missense variants in 24 ALS-associated genes. The two sequencing datasets were interrogated for missense variants in the 24 genes, and variants were annotated with gnomAD minor allele frequencies, ClinVar pathogenicity classifications, protein sequence features including Uniprot functional site annotations, and PhosphoSitePlus post-translational modification site annotations, structural features from AlphaFold predicted monomeric 3D structures, and transcriptomic expression levels from Genotype-Tissue Expression. We then applied missense variant enrichment and gene-burden testing following binning of variation based on the selected proteomic and transcriptomic features to identify those most relevant to pathogenicity in ALS-associated genes. Using predicted human protein structures from AlphaFold, we determined that missense variants carried by individuals with ALS were significantly enriched in ß-sheets and α-helices, as well as in core, buried or moderately buried regions. At the same time, we identified that hydrophobic amino acid residues, compositionally biased protein regions and regions of interest are predominantly enriched in missense variants carried by individuals with ALS. Assessment of expression level based on transcriptomics also revealed enrichment of variants of high and medium expression across all tissues and within the brain. We further explored enriched features of interest using burden analyses and identified individual genes were indeed driving certain enrichment signals. A case study is presented for SOD1 to demonstrate proof-of-concept of how enriched features may aid in defining variant pathogenicity. Our results present proteomic and transcriptomic features that are important indicators of missense variant pathogenicity in ALS and are distinct from features associated with neurodevelopmental disorders.

Rare neurovascular genetic and imaging markers across neurodegenerative diseases.

INTRODUCTION: Cerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)-based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status. METHODS: The Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non-synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1). RESULTS: NOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood. DISCUSSION: Further studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases.

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. Participants were clinically assessed and had gait performance assessed under single- and dual-task conditions. Structural neuroimaging data were analyzed to measure both, white matter hyperintensity (WMH) and normal appearing volumes. Percentage of WMH volume in frontal, parietal, occipital, and temporal lobes as well as subcortical hyperintensities in basal ganglia + thalamus were the main outcomes. Multivariate models investigated associations between DTC and hyperintensity volumes, adjusted for age, sex, years of education, global cognition, vascular risk factors, APOE4 genotype, residual sensorimotor symptoms from previous stroke and brain volume. RESULTS: There was a significant positive global linear association between DTC and hyperintensity burden (adjusted Wilks' λ = .87, P = .01). Amongst all WMH volumes, hyperintensity burden from basal ganglia + thalamus provided the most significant contribution to the global association (adjusted ß = .008, η2 = .03; P = .04), independently of brain atrophy. CONCLUSIONS: In poststroke, increased DTC may be an indicator of larger white matter damages, specifically in subcortical regions, which can potentially affect the overall cognitive processing and decrease gait automaticity by increasing the cortical control over patients' locomotion.

Clinical testing panels for ALS: global distribution, consistency, and challenges.

Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS. Methods: We reviewed the National Institutes of Health (NIH) Genetic Testing Registry (GTR) and members of the ALS GCEP to source frequently used testing panels and compare the genes included on the tests. Results: 14 clinical panels specific to ALS from 14 laboratories covered 4 to 54 genes. All panels report on ANG, SOD1, TARDBP, and VAPB; 50% included or offered the option of including C9orf72 hexanucleotide repeat expansion (HRE) analysis. Of the 91 genes included in at least one of the panels, 40 (44.0%) were included on only a single panel. We could not find a direct link to ALS in the literature for 14 (15.4%) included genes. Conclusions: The variability across the surveyed clinical genetic panels is concerning due to the possibility of reduced diagnostic yields in clinical practice and risk of a missed diagnoses for patients. Our results highlight the necessity for consensus regarding the appropriateness of gene inclusions in clinical genetic ALS tests to improve its application for patients living with ALS and their families.

Cost-effectiveness of a gene sequencing test for Alzheimer's disease in Ontario.

Alzheimer's f disease (AD) affects approximately 250,000 Ontarians, a number that is expected to double by 2040. The Ontario Neurodegenerative Disease Research Initiative has developed an in-province genetic test (ONDRISeq), which currently runs in Ontario in an experimental capacity. The aim of this study is to estimate the costs and health outcomes associated with ONDRISeq to diagnose AD relative to out-of-country (OOC) testing (status quo). A cost-utility analysis was developed for a hypothetical cohort of 65-year-olds at risk of AD in Ontario over a 25-year time horizon. Costs and health outcomes (quality-adjusted life years (QALYs)) were assessed from a healthcare payer perspective. Cost-effectiveness was assessed with a $50,000 cost-effectiveness threshold. Probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty. ONDRISeq saved $54 per patient relative to OOC testing and led to a small QALY gain in the base case (0.0014 per patient). Results were most sensitive to testing costs, uptake rates, and treatment efficacy. ONDRISeq represented better value for money relative to OOC testing throughout 75% of 10,000 probabilistic iterations. Using ONDRISeq is expected to provide health system cost savings. Switching to ONDRISeq for AD genetic testing in Ontario would be dependent on the ability to accommodate the expected testing volumes.

Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke.

Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME] and 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME] and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (ß=0.251, P=0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (ß=0.266, P=0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (ß=0.364, P<0.001; ß=0.362, P<0.001) and white matter MRI-visible perivascular spaces (ß=0.302, P=0.011; ß=0.314, P=0.006). In small vessel stroke, the 12,13-DiHOME/12(13)-EpOME ratio was associated with higher white matter free water diffusion (ß=0.439, P=0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10-DiHOME/9(10)-EpOME ratio was associated with temporal lobe atrophy (ß=-0.277, P=0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble-epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular-glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Targeted copy number variant identification across the neurodegenerative disease spectrum.

BACKGROUND: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. METHODS: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). RESULTS: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1-5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7-11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. CONCLUSION: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.

Lack of association of TP73 with amyotrophic lateral sclerosis in a large cohort of cases.

A recent study suggested an association between rare, non-synonymous variants in the gene encoding tumor protein p73 (TP73) and amyotrophic lateral sclerosis (ALS) - a progressive, fatal neurodegenerative disease. The original association was based on a case-control analysis with relatively small sample size. While functional data were presented to substantiate these claims, it remains unclear whether the results demonstrate clinical significance; additionally, the modelled null alleles had been recently reported to cause a severe pediatric disorder characterized by impaired mucociliary clearance and lissencephaly. Here, we aimed to replicate the proposed genetic association between TP73 and ALS using the two largest publicly available ALS sequencing datasets as hosted by the ALS Knowledge Portal (n = 3864 cases and n = 7839 controls) and the Project MinE ALS browser (n = 4366 cases and n = 1832 controls) for a total of 8230 ALS cases and 9671 controls. We did not observe an enrichment of rare, protein-coding variants in the ALS cases and surprisingly identified a relatively large number of controls carrying rare, non-synonymous variants in TP73 (n = 65). Based on these results we conclude that TP73 most likely does not predispose to ALS.

DnaJC7 in Amyotrophic Lateral Sclerosis.

Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents protein misfolding under normal conditions and, particularly, when cells experience protein folding stress due to the fact of increased levels of reactive oxygen species, genetic mutations, or aging. Molecular chaperones can prevent protein misfolding, refold misfolded proteins, or triage misfolded proteins for degradation by the ubiquitin-proteasome system or autophagy. DnaJC7 is an evolutionarily conserved molecular chaperone that contains both a J-domain for the interaction with Hsp70s and tetratricopeptide domains for interaction with Hsp90, thus joining these two major chaperones' machines. Genetic analyses reveal that pathogenic variants in the gene encoding DnaJC7 cause familial and sporadic ALS. Yet, the underlying ALS-associated molecular pathophysiology and many basic features of DnaJC7 function remain largely unexplored. Here, we review aspects of DnaJC7 expression, interaction, and function to propose a loss-of-function mechanism by which pathogenic variants in DNAJC7 contribute to defects in DnaJC7-mediated chaperoning that might ultimately contribute to neurodegeneration in ALS.

Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases.

Sex-stratified RNA-seq analysis reveals traumatic brain injury-induced transcriptional changes in the female hippocampus conducive to dementia.

Introduction: Traumatic brain injury (TBI), resulting from a violent force that causes functional changes in the brain, is the foremost environmental risk factor for developing dementia. While previous studies have identified specific candidate genes that may instigate worse outcomes following TBI when mutated, TBI-induced changes in gene expression conducive to dementia are critically understudied. Additionally, biological sex seemingly influences TBI outcomes, but the discrepancies in post-TBI gene expression leading to progressive neurodegeneration between the sexes have yet to be investigated. Methods: We conducted a whole-genome RNA sequencing analysis of post-mortem brain tissue from the parietal neocortex, temporal neocortex, frontal white matter, and hippocampus of 107 donors characterized by the Aging, Dementia, and Traumatic Brain Injury Project. Our analysis was sex-stratified and compared gene expression patterns between TBI donors and controls, a subset of which presented with dementia. Results: We report three candidate gene modules from the female hippocampus whose expression correlated with dementia in female TBI donors. Enrichment analyses revealed that the candidate modules were notably enriched in cardiac processes and the immune-inflammatory response, among other biological processes. In addition, multiple candidate module genes showed a significant positive correlation with hippocampal concentrations of monocyte chemoattractant protein-1 in females with post-TBI dementia, which has been previously described as a potential biomarker for TBI and susceptibility to post-injury dementia. We concurrently examined the expression profiles of these candidate modules in the hippocampus of males with TBI and found no apparent indicator that the identified candidate modules contribute to post-TBI dementia in males. Discussion: Herein, we present the first sex-stratified RNA sequencing analysis of TBI-induced changes within the transcriptome that may be conducive to dementia. This work contributes to our current understanding of the pathophysiological link between TBI and dementia and emphasizes the growing interest in sex as a biological variable affecting TBI outcomes.

Contribution of rare variant associations to neurodegenerative disease presentation.

Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson's disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.

Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses.

For many years there has been uncertainty regarding how apolipoprotein E (APOE) E2 and E4 variants may influence overlapping features of neurodegeneration, such as cognitive impairment. We aimed to identify whether the APOE variants are associated with cognitive function across various neurodegenerative and cerebrovascular diagnoses (n = 513). Utilizing a comprehensive neuropsychology battery, multivariate multiple regression was used to assess the influence of APOE carrier status and disease cohort on performance across five cognitive domains. Irrespective of disease cohort, E4 carriers had significantly lower performance in verbal memory and visuospatial domains than those with E3/3, while E2 carriers' cognitive performance was not significantly different. However, E2 carriers with frontotemporal dementia (FTD) performed significantly worse than those with E3/3 in the attention/working memory, executive function, and visuospatial domains. Our results highlight that the influence of APOE variation on cognition is complex, in some cases varying based on diagnosis and possibly underlying disease pathology.

Ancestry-specific profiles of genetic determinants of severe hypertriglyceridemia.

BACKGROUND: Susceptibility to severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) levels ≥10 mmol/L (880 mg/dL), is conferred by both heterozygous rare variants in five genes involved in TG metabolism and numerous common single-nucleotide polymorphisms (SNPs) associated with TG levels. OBJECTIVE: To date, these genetic susceptibility factors have been comprehensively assessed primarily in severe HTG patients of European ancestry. Here, we expand our analysis to HTG patients of East Asian and Hispanic ancestry. METHODS: The genomic DNA of 336, 63 and 199 severe HTG patients of European, East Asian and Hispanic ancestry, respectively, was evaluated using a targeted next-generation sequencing panel to screen for: 1) rare variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1; 2) common, small-to-moderate effect SNPs, quantified using a polygenic score; and 3) common, large-effect polymorphisms, APOA5 p.G185C and p.S19W. RESULTS: While the proportion of individuals with high polygenic scores was similar, frequency of rare variant carriers varied across ancestries. Compared with ancestry-matched controls, Hispanic patients were the most likely to have a rare variant (OR = 5.02; 95% CI 3.07-8.21; p < 0.001), while European patients were the least likely (OR = 2.56; 95% CI 1.58-4.13; p < 0.001). The APOA5 p.G185C polymorphism, exclusive to East Asians, was significantly enriched in patients compared with controls (OR = 10.1; 95% CI 5.6-18.3; p < 0.001), showing the highest enrichment among the measured genetic factors. CONCLUSION: While TG-associated rare variants and common SNPs are both found in statistical excess in severe HTG patients of different ancestral backgrounds, the overall genetic profiles of each ancestry group were distinct.

A novel homozygous variant in REN in a family presenting with classic features of disorders involving the renin-angiotensin pathway, without renal tubular dysgenesis.

Autosomal recessively inherited pathogenic variants in genes associated with the renin-angiotensin-aldosterone system (RAAS) result in early onset oligohydramnios and clinical features of the Potter sequence, typically in association with proximal renal tubules dysgenesis. We describe two siblings and a first cousin who had severe oligohydramnios in the second trimester, and presented at birth with loose skin, wide fontanelles and sutures, and pulmonary insufficiency. Two had refractory hypotension during their brief lives and one received palliative care after birth. All were found to have a homozygous nonsense variant, REN: c.891delG; p.Tyr287*, on exome sequencing. Autopsy limited to the genitourinary system in two of the children revealed normal renal tubular histology in both. Immunoblotting confirmed diminished expression of renin within cultured skin fibroblasts. To our knowledge, this is the first identification of an association between biallelic variants in REN and oligohydramnios in the absence of renal tubular dysgenesis. Due to its role in the RAAS, it has previously been proposed that the decreased expression of REN results in hypotension, ischemia, and decreased urine production. We suggest sequencing of genes in the RAAS, including REN, should be considered in cases of severe early onset oligohydramnios, even when renal morphology and histology are normal.

Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities.

BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease. METHODS: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort. RESULTS: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2). CONCLUSION: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition. © 2020 International Parkinson and Movement Disorder Society.