Phenotype in Individuals with Heterozygous Rare Variants in Encoding Hepatic Lipase.

Hepatic lipase deficiency is a rare genetic condition caused by biallelic loss-of-function variants in the gene encoding hepatic lipase. These variants reduce or abolish the protein's lipolytic activity, resulting in elevated plasma lipids. The condition is classified as autosomal recessive, since dyslipidemia is inconsistently observed in heterozygous patients with only one variant.

Reduced lipoprotein (a) in patients with severe hypertriglyceridaemia.

Objective: To investigate the relationship between plasma lipoprotein (a) (Lp[a]) and lipid profiles in patients with severe hypertriglyceridaemia (HTG).

Methods: This case-control study undertook a retrospective chart review of patients from the Lipid Genetics Clinic at London Health Sciences Centre in Ontario, Canada. Plasma Lp(a) was compared between patients with severe HTG and healthy normolipidaemic control subjects.

Comparison of patients with familial chylomicronemia syndrome and multifactorial chylomicronemia syndrome.

Context: Patients with rare familial chylomicronemia syndrome (FCS) and relatively common multifactorial chylomicronemia syndrome (MCS) both express severe hypertriglyceridemia, defined as plasma triglyceride concentration ≥10 mmol/L (≥885 mg/dL). Clinically there can be confusion between the two conditions.

Objective: To compare clinical and biochemical phenotypes in patients with genotypically characterized FCS and MCS.

Vascular calcification in chronic kidney disease associated with pathogenic variants in ABCC6.

Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10-20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD).

Carotid intima-medial thickness in patients with severe hypertriglyceridemia.

Background And Aims: Severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) concentration > 10 mmol/L, is relatively uncommon, and its implications for atherosclerotic cardiovascular disease (ASCVD) risk remain somewhat unclear. We evaluated the association between severe HTG and carotid intima-media thickness (IMT), a marker for ASCVD.

Methods: We studied three clinical cohorts: 88 patients with severe HTG (mean TG level 20.

Lipoprotein(a) in Familial Hypercholesterolemia.

Background: Low density lipoprotein (LDL) and Lipoprotein (Lp)(a) are proatherogenic apolipoprotein (apo) B-containing members of the non-high-density lipoprotein (non-HDL) family of particles. Elevated plasma levels of LDL cholesterol (C), non-HDL-C, and apo B are defining features of heterozygous familial hypercholesterolemia (HeFH), but reports of elevated plasma Lp(a) concentration are inconsistent.

Methods: We performed retrospective chart reviews of 256 genetically characterized patients with hypercholesterolemia and 272 control subjects from the Lipid Genetics Clinic at University Hospital in London, Ontario.

Variability of longitudinal triglyceride phenotype in patients heterozygous for pathogenic APOA5 variants.

Background: Biallelic pathogenic variants in APOA5 are an infrequent cause of familial chylomicronemia syndrome characterized by severe, refractory hypertriglyceridemia (HTG), and fasting plasma triglyceride (TG) >10 mmol/L (>875 mg/dL). The TG phenotype of heterozygous individuals with one copy of a pathogenic APOA5 variant is less familiar. We evaluated the longitudinal TG phenotype of individuals with a single pathogenic APOA5 variant allele.

Genetic Variants Associated with Severe Hypertriglyceridemia: LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE.

Objective: High triglyceride (TG) levels are associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD) and pancreatitis. The objectives for this study were to evaluate for the coexistence of severe HTG and pancreatitis in two different geographic regions of Turkey and to identify rare variants that cause monogenic HTG in our country.

Methods: In our study from 2014 to 2019, patients with severe HTG who presented to the endocrinology outpatient clinics with TG levels >500 mg/dL (5.

The longitudinal triglyceride phenotype in heterozygotes with LPL pathogenic variants.

Background: Biallelic pathogenic variants in lipoprotein lipase (LPL) cause familial chylomicronemia syndrome with severe hypertriglyceridemia (HTG), defined as plasma triglycerides (TG) > 10 mmol/L (> 885 mg/dL). TG levels in individuals with one copy of a pathogenic LPL gene variant is less familiar; some assume that the phenotype is intermediate between homozygotes and controls.

Objective: We undertook an evaluation of the longitudinal TG phenotype of individuals heterozygous for pathogenic LPL variants.

Unit Sales Trends of Hip Arthroplasty Procedures Performed in Ontario in 2020.

Background: In March 2020, an emergency was declared in the province of Ontario owing to the COVID-19 pandemic. From March 19 to May 26, all elective total hip arthroplasty (THA) and total knee arthroplasty (TKA) procedures were deferred. The purpose of this study was to review the unit sales data of THA and TKA procedures in Ontario over this time period to identify any trends in surgical activity.

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).

Prevalence of severe hypertriglyceridemia and pancreatitis in familial partial lipodystrophy type 2.

Familial partial lipodystrophy (FPLD) is a rare Mendelian condition listed in the differential diagnosis of severe hypertriglyceridemia (HTG) and pancreatitis. Here we determined the prevalence of severe HTG and pancreatitis among a cohort of 74 FPLD patients assessed in a lipid clinic. We studied lipid profiles from individuals with either of the two most common pathogenic monoallelic variants in LMNA, namely p.

Evaluating Polygenic Risk Scores in "Lone" Atrial Fibrillation.

Background: Polygenic scores incorporating varying numbers of single nucleotide polymorphisms (SNPs) have been demonstrated to exert a prominent role in atrial fibrillation (AF). We sought to compare the relative discriminatory capacities of 2 previously validated polygenic scores in "lone" AF.

Methods: A total of 186 lone AF cases of European ancestry underwent SNP genotyping.

Abetalipoproteinemia Due to a Novel Splicing Variant in in 3 Siblings.

Abetalipoproteinemia (ABL) is a rare recessive condition caused by biallelic loss-of-function mutations in the gene encoding the microsomal triglyceride transfer protein large subunit. ABL is characterized by absence of apolipoprotein B-containing lipoproteins and deficiencies in fat-soluble vitamins leading to multisystem involvement of which neurological complications are the most serious. We present 3 siblings with ABL who were born to non-consanguineous parents of Filipino and Chinese background.

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.

Clinical and Mutation Spectra of Cockayne Syndrome in India.

Background: Cockayne syndrome is an autosomal recessive disorder caused by biallelic mutations in ERCC6 or ERCC8 genes.

Aims: To study the clinical and mutation spectrum of Cockayne syndrome.

Setting And Design: Medical Genetics Outpatient Department of Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow.

Enrichment of loss-of-function and copy number variants in ventricular cardiomyopathy genes in 'lone' atrial fibrillation.

Aims: Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in ventricular cardiomyopathy in 'lone' AF.

Methods And Results: Whole-exome sequencing was performed in 255 early onset 'lone' AF cases, defined as arrhythmia onset prior to 60 years of age in the absence of known clinical risk factors.

Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype.

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), can be clinically heterogeneous which may be explained by the co-inheritance of multiple genetic variants that modify the clinical course. In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revealed a p.

Interrogation of selected genes influencing serum LDL-Cholesterol levels in patients with well characterized NAFLD.

Background: The clinical significance of rare mutations in LDL metabolism genes on nonalcoholic fatty liver disease (NAFLD) severity is not well understood.

Objective: To examine the significance of mutations in LDL metabolism genes including apolipoprotein B (APOB), proprotein convertase subtilisin kexin 9 (PCSK9) and LDL receptor (LDLR) in patients with NAFLD.

Methods: Patients with biopsy-confirmed NAFLD from the NASH Clinical Research Network studies were stratified into 3 groups of LDL-C (≤50 mg/dL, 130-150 mg/dL, ≥ 190 mg/dL) and then 120 (40 per group) were randomly selected from the strata.

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.

Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia.

Background: Combined hyperlipidemia (CHL) is a common disorder defined by concurrently elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Despite decades of study, the genetic basis of CHL remains unclear.

Objective: To characterize the genetic profiles of patients with CHL and compare them to those in patients with isolated hypercholesterolemia and isolated hypertriglyceridemia (HTG).

Simplifying Detection of Copy-Number Variations in Maturity-Onset Diabetes of the Young.

Objectives: Copy-number variations (CNVs) are large-scale deletions or duplications of DNA that have required specialized detection methods, such as microarray-based genomic hybridization or multiplex ligation probe amplification. However, recent advances in bioinformatics have made it possible to detect CNVs from next-generation DNA sequencing (NGS) data. Maturity-onset diabetes of the young (MODY) 5 is a subtype of autosomal-dominant diabetes that is often caused by heterozygous deletions involving the HNF1B gene on chromosome 17q12.