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IMPORTANCEUnexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined.OBJECTIVE To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes. DESIGN, SETTING, AND PARTICIPANTSThis genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021. MAIN OUTCOMES AND MEASURESThe frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD. RESULTSThe median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants. CONCLUSIONS AND RELEVANCEIn this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

Background: Thalassemia is a group of inherited blood disorders in which genetic mutation(s) in the α- and/or β-globin locus lead to excess precipitation of β- or α-globin, respectively, and compromised red blood cell (RBC) survival. The condition is characterized by ineffective erythropoiesis and peripheral hemolysis, with resultant anemia. Adenosine triphosphate (ATP) supply appears to be insufficient in thalassemic RBCs to maintain RBC membrane fitness and clearance of globin precipitates. Mitapivat (AG-348) is an oral, small-molecule, allosteric activator of the RBC-specific form of pyruvate kinase (PK-R). PK-R is a key enzyme for maintaining energy homeostasis in RBCs, as they rely almost exclusively on the process of glycolysis to generate ATP. In healthy adults, mitapivat activates wild-type PK-R and increases ATP levels in RBCs. In adults with PK deficiency who were not regularly transfused, oral mitapivat was well tolerated and induced rapid, durable hemoglobin (Hb) increases (NCT02476916). In the Hbbth/3+ mouse model of β-thalassemia, mitapivat increased ATP levels; reduced markers of ineffective erythropoiesis; and improved anemia, RBC survival, and indices of iron overload. These data support the hypothesis that increased ATP synthesis mediated via PK-R activation by mitapivat may improve the survival of thalassemic RBCs in the bone marrow and/or peripheral circulation, and thus represents a novel mechanism to treat patients with thalassemia. Here we present the design of a phase 2, open-label study designed to test this hypothesis and assess the proof of concept of mitapivat in patients with thalassemia. Methods: This phase 2, multicenter, open-label study (NCT03692052) is evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of mitapivat in adults with non-transfusion-dependent thalassemia (NTDT). Four sites in North America and the United Kingdom are enrolling patients. The study consists of a 24-week core period followed by a 2-year extension period (Figure). Approximately 17 subjects with NTDT, i.e., β-thalassemia with or without α-globin gene mutations, HbE β-thalassemia, or α-thalassemia (HbH disease), will be enrolled. Non-transfusion dependence is defined as ≤5 units of RBCs transfused in the preceding 24 weeks and no transfusions in the 8 weeks prior to the first day of study drug. The hemoglobin inclusion criterion is ≤10.0 g/dL, which was increased from ≤9.0 g/dL in a recent protocol amendment to better reflect the clinical representation in the NTDT patient population. All eligible patients will receive an initial mitapivat dose of 50 mg twice daily (BID). At the week 6 visit the dose may be increased to 100 mg BID, depending on safety and Hb response. The primary endpoint is the proportion of subjects who achieve an Hb response, defined as an increase in Hb of ≥1.0 g/dL from baseline at any time between week 4 and week 12 (inclusive). Key secondary and exploratory endpoints include changes in Hb and markers of hemolysis; hematopoietic activity; iron metabolism and iron overload; and assessments of safety and pharmacokinetics. The study is currently enrolling. Figure Disclosures Kuo: Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Layton:Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Uhlig:Agios: Employment, Equity Ownership. Lynch:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Vichinsky:GBT: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Agios: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Background - In population-based research exome sequencing (ES), the path from variant discovery to return of results (rROR) is not well established. Variants discovered by research ES have the potential to improve population health. Methods - Population-based ES and agnostic ExWAS were performed 5,521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a KCNQ1 variant from VUS to pathogenic. Results were returned to participants in a community setting. Results - A missense variant was identified in KCNQ1 (c.671C>T, p.T224M), a gene associated with long QT syndrome (LQTS) type 1 (LQT1), which can cause syncope and sudden cardiac death (SCD). The p.T224M variant, present in 1/45 Amish individuals is rare in the general population (1/248,566 in gnomAD) and was highly associated with QTc on EKG (p = 5.53E-24, β=20.2 ms/allele). Because of the potential importance of this variant to the health of the population, additional phenotyping was performed in 88 p.T224M carriers and 54 non-carriers. There was stronger clinical evidence of LQTS in carriers (38.6% vs 5.5%, p = 0.0006), greater history of syncope (32% vs 17%, p = 0.020), and higher rate of SCD in 1 st degree relatives < age 30 (4.5% vs 0%, p = 0.026). Expression of p.T224M KCNQ1 in CHO cells showed near complete loss of protein function. Our clinical and functional data enabled reclassification of p.T224M from a variant of unknown significance (VUS) to pathogenic. Of the 88 carriers, 93% met criteria for beta-blocker treatment and 5/88 (5.7%) were on medications that may further prolong QTc. Carriers were provided a CLIA confirmed report, genetic counseling and treatment recommendations. Follow up care was coordinated with local physicians. Conclusions - This work provides a framework by which research ES can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health.

Founder populations may be enriched with certain genetic variants of high clinical impact compared to nonfounder populations due to bottleneck events and genetic drift. Using exome sequencing (ES), we quantified the load of pathogenic variants that may be clinically actionable in 6136 apparently healthy adults living in the Lancaster, PA Old Order Amish settlement. We focused on variants in 78 genes deemed clinically actionable by the American College of Medical Genetics and Genomics (ACMG) or Geisinger's MyCode Health Initiative. ES revealed 3191 total variants among these genes including 480 nonsynonymous variants. After quality control and filtering, we applied the ACMG/AMP guidelines for variant interpretation and classified seven variants, across seven genes, as either pathogenic or likely pathogenic. Through genetic drift, all seven variants, are highly enriched in the Amish compared to nonfounder populations. In total, 14.7% of Lancaster Amish individuals carry at least one of these variants, largely explained by the 13% who harbor a copy of a single variant in APOB. Other studies report combined frequencies of pathogenic/likely pathogenic (P/LP) variants in actionable genes between 2.0% and 6.2% in outbred populations. The Amish population harbors fewer actionable variants compared to similarly characterized nonfounder populations but have a higher frequency of each variant identified, offering opportunities for efficient and cost‐effective targeted precision medicine.