Inferred inheritance of MorbidMap genes without OMIM clinical synopsis.

PurposeThe Genomic Oligoarray and SNP Array Evaluation Tool 3.0 matches candidate genes within regions of homozygosity with a patient's phenotype, by mining OMIM for gene entries that contain a Clinical Synopsis. However, the tool cannot identify genes/disorders whose OMIM entries lack a descriptor of the mode of (Mendelian) inheritance. This study aimed to improve the tool's diagnostic power by building a database of autosomal recessive diseases not diagnosable through OMIM.MethodsWe extracted a list of all genes in OMIM that produce disease phenotypes but lack Clinical Synopses or other statements of mode of inheritance. We then searched PubMed for literature regarding each gene in order to infer its inheritance pattern.ResultsWe analyzed 1,392 genes. Disorders associated with 372 genes were annotated as recessive and 430 as dominant. Autosomal genes were ranked from 1 to 3, with 3 indicating the strongest evidence behind the inferred mode of inheritance. Of 834 autosomal genes, 158 were ranked as 1, 228 as 2, and 448 as 3.ConclusionThe 372 genes associated with recessive disorders will be contributed to the SNP array tool, and the entire database to OMIM. We anticipate that these findings will be useful in rare disease diagnostics.

Qualitative and Quantitative Effects of PCSK9 Inhibitors in familial Hypercholesterolemia: a Synthetic Review.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused most commonly by mutations in the gene coding for LDL receptors. This results in increased circulating cholesterol, and clinical consequences of premature stroke, myocardial infarction, etc. FH remains underdiagnosed and thus undertreated, leading to a high health care burden. A newer group of agents, the PCSK9 inhibitors, effectively reduces plasma cholesterol, especially when combined with other lipid lowering agents. The purpose of this narrative review is to synthesize all existing qualitative and quantitative data on the utility of PCSK9 inhibitors in familial hypercholesterolemia, in order to clarify standards of care and identify areas needing further research. Through PubMed/MEDLINE keyword searching, we identified 12 existing randomized controlled trials comparing PCSK9 inhibitor to placebo in FH patients, and pooled their outcomes across a total 2533 patients. We also reviewed quantitative effect on ASCVD outcomes and cost/benefit ratios. In FH patients, PCSK9 inhibitors caused a mean LDL reduction of -49.1%, compared to -3.5% with placebo (weighted average was calculated to account for different study sizes). These findings are comparable to trial results in the non-FH ASCVD population. However, there are no data on PCSK9 inhibitors' effect on hard cardiovascular outcomes in FH. Furthermore, in order for PCSK9 inhibitors to qualify as high-value care, price must be significantly reduced or LDL goals increased. PCSK9 inhibitors are potent reducers of LDL in FH patients. However, dedicated randomized trials are needed to assess whether this translates into statistically significant ASCVD prevention long-term.

Wide Complex Tachycardia in a Right-Sided Heart: Diagnostic and Therapeutic Challenges.

Dextroposition is a rare cardiac malformation defined as heart shift to right of midline. ECG findings vary with degree of displacement within the chest cavity. We report the second known case of dextroposition with accessory pathway (posteroseptal in our patient), presenting as pre-excited atrial tachycardia. Abnormal anatomy complicates pathway localization/ablation. (Level of Difficulty: Intermediate.).

Dual therapy with oral anticoagulation and single antiplatelet agent versus monotherapy with oral anticoagulation alone in patients with atrial fibrillation and stable ischemic heart disease: a systematic review and meta-analysis.

BACKGROUND: In patients with atrial fibrillation (AF) and stable ischemic heart disease, recent guidelines recommend oral anticoagulant (OAC) monotherapy in preference to OAC + single antiplatelet agent (SAPT) dual therapy. However, these data are based on the results of only two randomized controlled trials (RCTs) and a relatively small group of patients. Thus, the safety and efficacy of this approach may be underpowered to detect a significant difference. We hypothesized that OAC monotherapy will have a reduced risk of bleeding, but similar all-cause mortality and ischemic outcomes as compared to dual therapy (OAC + SAPT). METHODS: A systematic search of PubMed/MEDLINE, EMBASE, and Scopus was conducted. Safety outcomes included total bleeding, major bleeding, and others. Efficacy outcomes included all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and major adverse cardiovascular events (MACE). RCTs and observational studies were pooled separately (study design stratified meta-analysis). Subgroup analyses were performed for vitamin K antagonists and direct oral anticoagulants (DOACs). Pooled risk ratios (RR) with corresponding 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method. RESULTS: Meta-analysis of 2 RCTs comprising a total of 2905 patients showed that dual therapy (OAC + SAPT) vs. OAC monotherapy was associated with a statistically significant increase in major bleeding (RR 1.51; 95% CI [1.10, 2.06]). There was no significant reduction in MACE (RR 1.10; [0.71, 1.72]), stroke (RR 1.29; [0.85, 1.95]), myocardial infarction (RR 0.57; [0.28, 1.16]), cardiovascular mortality (RR 1.22; [0.63, 2.35]), or all-cause mortality (RR 1.18 [0.52, 2.68]). Meta-analysis of 20 observational studies comprising 47,451 patients showed that dual therapy (OAC + SAPT) vs. OAC monotherapy was associated with a statistically significant higher total bleeding (RR 1.50; [1.20, 1.88]), major bleeding (RR = 1.49; [1.38, 1.61]), gastrointestinal bleeding (RR = 1.62; [1.15, 2.28]), and myocardial infarction (RR = 1.15; [1.05, 1.26]), without significantly lower MACE (RR 1.10; [0.97, 1.24]), stroke (RR 0.93; [0.73, 1.19]), cardiovascular mortality (RR 1.11; [0.95, 1.29]), or all-cause mortality (RR 0.93; [0.78, 1.11]). Subgroup analysis showed similar results for both vitamin K antagonists and DOACs, except a statistically significant higher intracranial bleeding with vitamin K antagonist + SAPT vs. vitamin K antagonist monotherapy (RR 1.89; [1.36-2.63]). CONCLUSIONS: In patients with AF and stable ischemic heart disease, OAC + SAPT as compared to OAC monotherapy is associated with a significant increase in bleeding events without a significant reduction in thrombotic events, cardiovascular mortality, and all-cause mortality.

The enigmatic immunoglobulin G4-related disease and its varied cardiovascular manifestations.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disease characterised by multiorgan lymphoplasmacytic infiltration, obliterative phlebitis and storiform fibrosis. It can be associated with cardiovascular pathology. The objective of this narrative review is to summarise the published literature on cardiovascular manifestations of IgG4-RD and to provide a basis for diagnosis and management of the condition by the practising cardiologist.We propose the following categorisations of cardiovascular IgG4-RD: aortitis, medium-vessel arteritis, pulmonary vascular disease, phlebitis, valvulopathy, pericarditis, myocardial disease and antineutrophilic cytoplasmic antibody-associated vasculitis. We also review herein developments in radiological diagnosis and reported medical and surgical therapies. Cardiovascular lesions frequently require procedural and/or surgical interventions, such as aortic aneurysm repair and valve replacement. IgG4-RD of the cardiovascular system results in serious complications that can be missed if not evaluated aggressively. These are likely underdiagnosed, as clinical presentations frequently mimic cardiovascular disease due to more common aetiologies (myocardial infarction, abdominal aortic aneurysm and so on). While systemic corticosteroids are the mainstay of IgG4-RD treatment, biological and disease-modifying agents are becoming more widely used. Cardiologists should be aware of cardiovascular IgG4-RD as a differential diagnosis, and understand the roles of corticosteroids, disease-modifying agents and biologicals, as well as their integration with surgical approaches. There are several knowledge gaps, including diagnosis, risk factors, pathogenesis and appropriate management in Ig4-RD of the cardiovascular system. Areas lacking well-conducted randomized trials include safety of steroids in the setting of vascular aneurysms and the role of disease-modifying drugs and biological agents in patients with established cardiovascular complications of this multifaceted enigmatic disease.

Two Roads Diverge: Treatment Choice in Coexisting Severe Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria.

Aplastic anemia (AA) is a bone marrow failure syndrome of pancytopenia due to impaired hematopoiesis. It is strongly associated with paroxysmal nocturnal hemoglobinuria (PNH). Each condition can cause the other, or occur simultaneously. There are no guidelines for treating concomitant AA and PNH; immunosuppressive therapy (IST) or hematopoietic stem cell therapy (HSCT) is first-line for the former, and eculizumab is first-line for the latter. New studies suggest that treating AA/PNH together versus sequentially should depend on AA severity. We report the case of a previously healthy male (31-year-old, Nigerian immigrant) who developed jaundice, scleral icterus, easy fatigability, and epistaxis. He was diagnosed with AA on bone marrow biopsy and with PNH on flow cytometry. He initially underwent chemotherapy due to increased infection risk with eculizumab in a neutropenic patient; however, he showed minimal response and thus began eculizumab pending allogeneic stem cell transplant. There are no guidelines for treating patients with both AA and PNH, and clinical decision making is generally individualized based on disease severity. Only one prior publication reported simultaneous treatment with eculizumab and chemotherapy, due to stated concern for pancytopenia, especially neutropenia, being the most immediate cause of morbidity/mortality. This demonstrates the individualized decisions that must be made when treating simultaneous PNH and AA, and the importance of PNH/severe AA patients as a separate subpopulation.

The first case of deafness-dystonia syndrome due to compound heterozygous variants in FITM2.

We report the second known family affected by deafness-dystonia syndrome associated with loss of function of FITM2. Our patient is compound heterozygous for pathogenic FITM2 variants, while affected siblings in the first report were homozygous. This case provides evidence that this novel genetic disorder is associated with autosomal recessive inheritance.