Genetic testing in monogenic early-onset atrial fibrillation.

A substantial proportion of atrial fibrillation (AF) cases cannot be explained by acquired AF risk factors. Limited guidelines exist that support routine genetic testing. We aim to determine the prevalence of likely pathogenic and pathogenic variants from AF genes with robust evidence in a well phenotyped early-onset AF population. We performed whole exome sequencing on 200 early-onset AF patients. Variants from exome sequencing in affected individuals were filtered in a multi-step process, prior to undergoing clinical classification using current ACMG/AMP guidelines. 200 AF individuals were recruited from St. Paul's Hospital and London Health Sciences Centre who were ≤ 60 years of age and without any acquired AF risk factors at the time of AF diagnosis. 94 of these AF individuals had very early-onset AF ( ≤ 45). Mean age of AF onset was 43.6 ± 9.4 years, 167 (83.5%) were male and 58 (29.0%) had a confirmed family history. There was a 3.0% diagnostic yield for identifying a likely pathogenic or pathogenic variant across AF genes with robust gene-to-disease association evidence. This study demonstrates the current diagnostic yield for identifying a monogenic cause for AF in a well-phenotyped early-onset AF cohort. Our findings suggest a potential clinical utility for offering different screening and treatment regimens in AF patients with an underlying monogenic defect. However, further work is needed to dissect the additional monogenic and polygenic determinants for patients without a genetic explanation for their AF despite the presence of specific genetic indicators such as young age of onset and/or positive family history.

Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass.

Left ventricular mass is a risk marker for cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance is the gold-standard for left ventricular mass estimation, but is challenging to obtain at scale. Here, we use deep learning to enable genome-wide association study of cardiac magnetic resonance-derived left ventricular mass indexed to body surface area within 43,230 UK Biobank participants. We identify 12 genome-wide associations (1 known at TTN and 11 novel for left ventricular mass), implicating genes previously associated with cardiac contractility and cardiomyopathy. Cardiac magnetic resonance-derived indexed left ventricular mass is associated with incident dilated and hypertrophic cardiomyopathies, and implantable cardioverter-defibrillator implant. An indexed left ventricular mass polygenic risk score ≥90th percentile is also associated with incident implantable cardioverter-defibrillator implant in separate UK Biobank (hazard ratio 1.22, 95% CI 1.05-1.44) and Mass General Brigham (hazard ratio 1.75, 95% CI 1.12-2.74) samples. Here, we perform a genome-wide association study of cardiac magnetic resonance-derived indexed left ventricular mass to identify 11 novel variants and demonstrate that cardiac magnetic resonance-derived and genetically predicted indexed left ventricular mass are associated with incident cardiomyopathy.

Donor and recipient human leukocyte antigen-G polymorphisms modulate the risk of adverse immunologic events following lung transplantation.

The long-term benefits of lung transplantation (LTx) are limited by pathogenic alloimmune responses that drive injury, inflammation, and chronic dysfunction. Human leukocyte antigen-G (HLA-G) plays a key role in the modulation of these pathways. This study assesses the impact of the HLA-G genotype on immunologic risk and survival following LTx. This retrospective cohort study included 289 bilateral LTx. Recipient and donor HLA-G genotypes were analyzed to identify associations with de novo donor-specific antibodies, acute rejection, chronic lung allograft dysfunction, and allograft survival. We further assessed these associations, both individually and in paired analysis, based on a grouped haplotype classification of HLA-G expression. Donor HLA-G single nucleotide polymorphisms were associated with allograft injury, the onset of chronic lung allograft dysfunction following injury, and allograft survival. Recipient HLA-G single nucleotide polymorphisms were associated with allograft injury, cellular rejection, and donor-specific antibody formation. "Low HLA-G expression" donor haplotypes were associated with impaired allograft survival, as were "low HLA-G expression" donor-recipient haplotype pairs. This study provides compelling evidence for the role of HLA-G in modulating immunologic risk after LTx. Our results highlight the importance of both donor and recipient HLA-G genotypes on the overall risk profile and underscore the lasting influence of donor genotype on lung transplant outcomes.

LMNA Variants and Risk of Adult-Onset Cardiac Disease.

BACKGROUND: Genetic variants in LMNA may cause cardiac disease, but population-level contributions of variants to cardiac disease burden are not well-characterized. OBJECTIVES: We sought to determine the frequency and contribution of rare LMNA variants to cardiomyopathy and arrhythmia risk among ambulatory adults. METHODS: We included 185,990 UK Biobank participants with whole-exome sequencing. We annotated rare loss-of-function and missense LMNA variants for functional effect using 30 in silico prediction tools. We assigned a predicted functional effect weight to each variant and calculated a score for each carrier. We tested associations between the LMNA score and arrhythmia (atrial fibrillation, bradyarrhythmia, ventricular arrhythmia) or cardiomyopathy outcomes (dilated cardiomyopathy and heart failure). We also examined associations for variants located upstream vs downstream of the nuclear localization signal. RESULTS: Overall, 1,167 (0.63%) participants carried an LMNA variant and 15,079 (8.11%) had an arrhythmia or cardiomyopathy event during a median follow-up of 10.9 years. The LMNA score was associated with arrhythmia or cardiomyopathy (OR: 2.21; P < 0.001) and the association was more significant when restricted to variants upstream of the nuclear localization signal (OR: 5.05; P < 0.001). The incidence rate of arrhythmia or cardiomyopathy was 8.43 per 1,000 person-years (95% CI: 6.73-10.12 per 1,000 person-years) among LMNA variant carriers and 6.38 per 1,000 person-years (95% CI: 6.27-6.50 per 1,000 person-years) among noncarriers. Only 3 (1.2%) of the variants were reported as pathogenic in ClinVar. CONCLUSIONS: Middle-aged adult carriers of rare missense or loss-of-function LMNA variants are at increased risk for arrhythmia and cardiomyopathy.

Is Deprescription of Ezetimibe Safe in Familial Hypercholesterolemia Patients Taking Evolocumab?

We evaluated whether low-density lipoprotein cholesterol (LDL-C) levels in familial hypercholesterolemia patients on triple lipid-lowering therapy would remain below intensification threshold values after withdrawal of ezetimibe. We included 13 heterozygous familial hypercholesterolemia patients with vascular disease who were treated with statin + ezetimibe + evolocumab; ezetimibe was discontinued at the patients' request. After 3 months, LDL-C levels increased from 0.96 ± 0.51 to 1.54 ± 1.07 mmol/L. In 12 of 13 patients, the LDL-C level remained below 1.8 mmol/L. No adverse cardiovascular events were observed. Deprescribing ezetimibe reduced pill burden but increased LDL-C level, although usually not above the treatment intensification threshold for high-risk patients.

Nous avons évalué si les concentrations de cholestérol à lipoprotéines de faible densité (C-LDL) des patients atteints d'hypercholestérolémie familiale sur le traitement hypolipidémiant demeureraient en deçà des valeurs seuils d'intensification après le retrait de l'ézétimibe. Nous avons retenu 13 patients atteints d'une maladie vasculaire qui ont la forme hétérozygote d'hypercholestérolémie familiale et qui ont été traités par statine + ézétimibe + évolocumab; l'ézétimibe a été interrompu à la demande des patients. Après 3 mois, les concentrations de C-LDL sont passées de 0,96 ± 0,51 à 1,54 ± 1,07 mmol/l. Chez 12 des 13 patients, les concentrations de C-LDL sont demeurées en deçà de 1,8 mmol/l. Nous n'avons observé aucun événement cardiovasculaire indésirable. La déprescription de l'ézétimibe a permis de réduire le fardeau posologique, mais a entraîné l'augmentation des concentrations de C-LDL, bien qu'elles ne fussent généralement pas au-dessus du seuil d'intensification du traitement des patients exposés à un risque élevé.

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.R482Q (N= 51) and p.R482W (N= 23). In total, 28 (37.8%) patients with a mean age of 41.8 ± 14.8 years had diabetes, while 46 (62.2%) patients with a mean age of 35.4 ± 19.4 years had no diabetes. Among patients with and without diabetes, median TG levels (interquartile range) were 2.73 (4.78) and 1.86 (1.66) mmol/L (242 [423] and 165 [147] mg/dL), respectively. Overall, 4 subjects (5.4%) had triglyceride levels > 10 mmol/L (> 885 mg/dL), of whom 3 (4.1%) had a history of hospitalization for acute pancreatitis. All 4 patients with severe HTG had diabetes, i.e. 14.3% of those with diabetes. In contrast, FPLD2 patients without diabetes had only mild HTG, with no instances of severe HTG or pancreatitis. Thus, among this selected lipid clinic cohort with lipodystrophy, severe HTG and pancreatitis in FPLD2 are relatively common when diabetes is present.

Volanesorsen for treatment of familial chylomicronemia syndrome.

INTRODUCTION: Familial chylomicronemia syndrome (FCS) is a rare subtype of severe hypertriglyceridemia that affects ~1 in 100, 000 to 1,000,000 individuals. The major risk to health is acute pancreatitis. FCS is defined by biallelic loss-of-function mutations in one of five canonical genes that encode proteins critical to lipolysis of large triglyceride-rich lipoprotein particles. Unlike the vast majority of patients with severe hypertriglyceridemia, FCS patients lack any lipolytic capacity and are thus resistant to standard medications. AREAS COVERED: This review focuses on a mechanism that effectively reduces elevated triglyceride levels in FCS, namely interference of synthesis of apolipoprotein (apo) C-III. Volanesorsen is an antisense RNA drug administered subcutaneously that knocks down apo C-III, resulting in dramatic reductions in triglyceride levels both in FCS patients and in the wider population of subjects with severe hypertriglyceridemia. EXPERT OPINION: Volanesorsen is a highly effective treatment to reduce elevated triglycerides in FCS patients, providing proof-of-concept of the validity of targeting apo C-III. However, off target effects of volanesorsen, including thrombocytopenia, may ultimately limit its use. Nonetheless, building on the knowledge derived from the volanesorsen experience, there is intensified interest in promising newer agents that also target apo C-III but have technical modifications that limit potential off target adverse effects.

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. A genome-wide polygenic score (GPS) and polygenic risk score (PRS) involving 6,730,541 and 1168 SNPs, respectively, were calculated for 186 cases and 423 controls of European ancestry from the 1000 Genomes (1KG) Project. The distribution of the polygenic scores was compared between the cases and controls and their discriminatory capacities were evaluated using receiver operating characteristic (ROC) curves. RESULTS: A total of 34.4% of patients with lone AF had GPS scores greater than the top 10th percentile of 1KG controls, corresponding to a 4.64-fold increased odds (95% confidence interval [CI], 2.99-7.18; P < 0.001) for AF. A PRS score in the top 10th percentile of 1KG controls was observed in 26.3% of cases, which equated to a 3.16-fold increased odds (95% CI, 2.01-4.98; P < 0.001) for AF. Comparison of C-statistics from ROC curves indicated improved discriminatory capacity of the GPS (0.76) relative to the PRS (0.70) (P = 0.002). CONCLUSIONS: Our study evaluating 2 polygenic scores for AF suggests that the GPS, containing more than 6.7 million SNPs, exhibits an improved discriminatory capacity in lone AF compared with a PRS possessing 1168 SNPs. Our findings suggest that genetic risk scores for AF that maximally leverage genomic data may provide improved predictive power.

CONTEXTE: Il a été démontré que des scores polygéniques intégrant un nombre variable de polymorphismes mononucléotidiques (PMN) jouent un rôle important en ce qui concerne la fibrillation auriculaire (FA). Nous avons comparé le potentiel discriminatoire relatif de deux scores polygéniques déjà validés dans la FA idiopathique. MÉTHODOLOGIE: Au total, 186 sujets d'ascendance européenne atteints de FA idiopathique ont été soumis à un génotypage des PMN. Un score polygénique génomique (SPG) et un score de risque polygénique (SRP) comprenant respectivement 6 730 541 et 1 168 PMN ont été calculés pour les 186 sujets et pour 423 témoins d'ascendance européenne dont les données sont tirées du projet 1000 Genomes (1KG). Les distributions des scores polygéniques des sujets et des témoins ont été comparées, et leur potentiel discriminatoire a été évalué au moyen des courbes caractéristiques de la performance d'un test (courbes ROC, de l'anglais Receiver Operating Characteristic). RÉSULTATS: Au total, 34,4 % des patients atteints de FA idiopathique avaient un SPG supérieur à celui des témoins du 10e centile supérieur du projet 1KG, ce qui représente une probabilité de FA 4,64 fois plus élevée (intervalle de confiance [IC] à 95 % : 2,99 à 7,18; p < 0,001). Un SRP situé dans le 10e centile supérieur des témoins du projet 1KG a été observé chez 26,3 % des patients atteints de FA, soit une probabilité de FA 3,16 fois plus élevée (IC à 95 % : 2,01 à 4,98; p < 0,001). Les résultats de la comparaison des statistiques C des courbes ROC indiquent que le SPG (0,76) a un potentiel discriminatoire supérieur à celui du SRP (0,70) (p = 0,002). CONCLUSIONS: Les résultats de notre étude de deux scores polygéniques relatifs à la FA indiquent que le potentiel discriminatoire du SPG, qui comprend plus de 6,7 millions de PMN, pour prédire une FA idiopathique est supérieur à celui du SRP, qui comprend 1 168 PMN. Ces résultats indiquent que les scores de risque génétique de FA qui exploitent pleinement les données génomiques pourraient avoir un pouvoir prédictif supérieur.

Lipid effects of sodium-glucose cotransporter 2 inhibitors.

PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used antihyperglycemic drugs that show remarkable cardiorenal protective effects in patients with or without type 2 diabetes. Furthermore, they are effective among patients across a wide range of baseline renal and cardiac function. Numerous mechanisms have been evaluated to understand these remarkable clinical benefits. From an early stage, these agents were noted to affect the plasma lipid profile. Here we review lipid profile alterations attributable to SGLT2 inhibitors and also some mechanisms explored in model systems and human studies. RECENT FINDINGS: SGLT2 inhibitors given to patients with diabetes as monotherapy shift substrate utilization from carbohydrates to lipids, and have mild effects on the lipid profile. Increased LDL cholesterol appears to be associated with increased hepatic production and decreased catabolism. Increased HDL cholesterol and decreased triglycerides appear to be associated with improved insulin sensitivity and increased lipolysis. Lipid effects of SGLT2 inhibitors are further modulated by background therapy with other diabetes medications and statins. SUMMARY: The minor lipid profile alterations observed in patients treated with SGLT2 inhibitors are offset by the staggering range of beneficial pleiotropic mechanisms that likely explain the marked cardiorenal benefits of these agents.

Liver Injury Associated With Ezetimibe Monotherapy.

Statin intolerance, primarily myalgia, is not uncommon in patients treated for elevated low-density lipoprotein cholesterol. Nonstatin drugs, such as ezetimibe, can spare patients from statin exposure, while still reducing low-density lipoprotein cholesterol. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been occasionally reported. We describe an extremely rare case of an ezetimibe-associated liver injury who required protracted treatment with prednisone and azathioprine. Ezetimibe-associated liver injury should be suspected with development of hepatic abnormalities concurrent with the timing of ezetimibe treatment and in the absence of other possible precipitating factors.

L'intolérance aux statines, se manifestant principalement par une myalgie, n'est pas rare chez les patients traités pour des taux élevés de cholestérol à lipoprotéines à basse densité (LDL). Des médicaments n'appartenant pas à la classe des statines, comme l'ézétimibe, permettent d'éviter l'exposition aux statines chez les patients, tout en réduisant le taux le cholestérol LDL. L'ézétimibe est généralement bien toléré, bien que des symptômes gastro-intestinaux et musculosquelettiques aient été signalés à l'occasion. Nous décrivons un cas extrêmement rare de lésion hépatique associée à l'ézétimibe ayant nécessité un traitement prolongé par la prednisone et l'azathioprine. Il faut soupçonner une lésion hépatique liée à l'ézétimibe lors de la survenue d'anomalies hépatiques pendant le traitement par l'ézétimibe en l'absence d'autres facteurs déclencheurs.

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. Subsequent evaluations were restricted to 195 cases of European genetic ancestry, as defined by principal component analysis, and focused on a pre-defined set of 43 genes previously implicated in ventricular cardiomyopathy. Bioinformatic analysis identified 6 LOF variants (3.1%), including 3 within the TTN gene, among cases in comparison with 4 of 503 (0.80%) controls [odds ratio: 3.96; 95% confidence interval (CI): 1.11-14.2; P = 0.033]. Further, two AF cases possessed a novel heterozygous 8521 base pair TTN deletion, confirmed with Sanger sequencing and breakpoint validation, which was absent from 4958 controls (P = 0.0014). Subsequent cascade screening in two families revealed evidence of co-segregation of a LOF variant with 'lone' AF. CONCLUSION: 'Lone' AF cases are enriched in rare LOF variants from cardiomyopathy genes, findings primarily driven by TTN, and a novel TTN deletion, providing additional evidence to implicate atrial cardiomyopathy as an AF genetic sub-phenotype. Our results also highlight that AF may develop in the context of these variants in the absence of a discernable ventricular cardiomyopathy.

Cardiac ryanodine receptor calcium release deficiency syndrome.

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

Overview of the Canadian Clinician Investigator Trainees' research presented at the 2019 CSCI-CITAC Joint Meeting.

The 2019 Annual General Meeting and Young Investigators' Forum of the Canadian Society for Clinical Investigation / Société Canadienne de Recherche Clinique (CSCI/SCRC) and Clinician Investigator Trainee Association of Canada / Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was held in Banff, Alberta on November 8-10th, 2019. The theme was "Positioning Early Career Investigators for Success: Strategy and Resilience". Lectures and workshops provided knowledge and tools to facilitate the attendees' development as clinician investigators. Dr. Jason Berman (President of CSCI/SCRC), Elina Cook (President of CITAC/ACCFC) and Drs. Doreen Rabi and Zelma Kiss (University of Calgary Organizing Co-Chairs) gave opening presentations. The keynote speakers were Dr. William Foulkes (McGill University) (Distinguished Scientist Award winner) and Dr. Andrés Finzi (Université de Montréal) (Joe Doupe Young Investigator Award winner). Dr. Robert Bortolussi (Dalhousie University) received the Distinguished Service Award for his work as the Editor-in-Chief of Clinical and Investigative Medicine and for being instrumental in the development of the Canadian Child Health Clinician Scientist Program. This meeting was the first to host a panel discussion with Drs. Stephen Robbins and Marcello Tonelli from the Canadian Institutes of Health Research. Workshops on communication, career planning and work-life balance were hosted by André Picard and Drs. Todd Anderson, Karen Tang, William Ghali, May Lynn Quan, Alicia Polachek and Shannon Ruzycki. The AGM showcased 90 presentations from clinician investigator trainees from across Canada. Most of the abstracts are summarized in this review. Eight outstanding abstracts were selected for oral presentation at the President's Forum.

A cautionary tale: Is this APOB whole-gene duplication actually pathogenic?

A 22-year-old woman presented with elevated low-density lipoprotein (LDL) cholesterol and clinically suspected familial hypercholesterolemia. Initial genetic analysis by Sanger sequencing found no causal variants in LDLR or other familial hypercholesterolemia genes. More than a decade later, her 9-year-old daughter was also found to have elevated LDL cholesterol. Re-analysis using current genetic methodology detected a novel whole-gene duplication of APOB in both individuals, which was tentatively assumed to explain their elevated LDL cholesterol based mainly on biological plausibility. However, on further assessment with cascade screening and cosegregation analysis involving multiple family members, the APOB duplication was eventually discounted as being causative. This case illustrates the risk of assuming pathogenicity of a novel genetic variant without undertaking corroborative diagnostic measures. It further highlights the time and skill required for accurate variant analysis and emphasizes the challenges faced by clinicians who are increasingly expected to rapidly interpret such results without sufficient time or resources to pursue supportive or corroborating evidence.

Pediatric Dyslipidemia-Beyond Familial Hypercholesterolemia.

Dyslipidemia is seen with increasing prevalence in young Canadians, mainly mild to moderate hypertriglyceridemia secondary to obesity. This review focuses on pediatric dyslipidemias excluding familial hypercholesterolemia (FH), but including both severe and mild to moderate hypertriglyceridemia, combined hyperlipidemia, and elevated lipoprotein(a) [Lp(a)]. We suggest that for Canadian children and adolescents with dyslipidemia, atherosclerotic cardiovascular disease (ASCVD) risk assessment should include both low-density lipoprotein cholesterol and triglyceride measurement. To further stratify risk, determination of non-high-density lipoprotein cholesterol is recommended, for both its ability to predict ASCVD and convenience for the patient because fasting is not required. Similarly, apolipoprotein B measurement (fasting or nonfasting), where available, can be helpful. Lp(a) measurement should not be routine in childhood, but it can be considered in special circumstances. After ruling out secondary causes, the foundation for management of pediatric dyslipidemia includes weight regulation, optimizing diet, and increasing activity level. At present, randomized clinical trial data to guide pharmaceutical management of pediatric hypertriglyceridemia or other non-FH pediatric dyslipidemias are scarce. Pharmaceutical management should be reserved for special situations in which risk of complications such as acute pancreatitis or ASCVD over the intermediate term is high and conservative lifestyle-based interventions have been ineffective.