Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program.

BACKGROUND: Malignant hyperthermia (MH) susceptibility is a heritable musculoskeletal disorder that can present as a potentially fatal hypermetabolic response to triggering anesthesia agents. Genomic screening for variants in MH-associated genes RYR1 and CACNA1S provides an opportunity to prevent morbidity and mortality. There are limited outcomes data from disclosing variants in RYR1, the most common MH susceptibility gene, in unselected populations. The authors sought to identify the rate of MH features or fulminant episodes after triggering agent exposure in an unselected population undergoing genomic screening including actionable RYR1 variants. METHODS: The MyCode Community Health Initiative by Geisinger (USA) is an electronic health record-linked biobank that discloses pathogenic and likely pathogenic variants in clinically actionable genes to patient-participants. Available electronic anesthesia and ambulatory records for participants with actionable RYR1 results returned through December 2020 were evaluated for pertinent findings via double-coded chart reviews and reconciliation. Descriptive statistics for observed phenotypes were calculated. RESULTS: One hundred fifty-two participants had an actionable RYR1 variant disclosed during the study period. None had previous documented genetic testing for MH susceptibility; one had previous contracture testing diagnosing MH susceptibility. Sixty-eight participants (44.7%) had anesthesia records documenting triggering agent exposure during at least one procedure. None received dantrolene treatment or had documented muscle rigidity, myoglobinuria, hyperkalemia, elevated creatine kinase, severe myalgia, or tea-colored urine. Of 120 possibly MH-related findings (postoperative intensive care unit admissions, hyperthermia, arterial blood gas evaluation, hypercapnia, or tachycardia), 112 (93.3%) were deemed unlikely to be MH events; 8 (6.7%) had insufficient records to determine etiology. CONCLUSIONS: Results demonstrate a low frequency of classic intraanesthetic hypermetabolic phenotypes in an unselected population with actionable RYR1 variants. Further research on the actionability of screening for MH susceptibility in unselected populations, including economic impact, predictors of MH episodes, and expanded clinical phenotypes, is necessary.

Innovative Implementation Strategies for Familial Hypercholesterolemia Cascade Testing: The Impact of Genetic Counseling.

The IMPACT-FH study implemented strategies (packet, chatbot, direct contact) to promote family member cascade testing for familial hypercholesterolemia (FH). We evaluated the impact of genetic counseling (GC) on medical outcomes, strategy selection, and cascade testing. Probands (i.e., patients with FH) were recommended to complete GC and select sharing strategies. Comparisons were performed for both medical outcomes and strategy selection between probands with or without GC. GEE models for Poisson regression were used to examine the relationship between proband GC completion and first-degree relative (FDR) cascade testing. Overall, 46.3% (81/175) of probands completed GC. Probands with GC had a median LDL-C reduction of -13.0 mg/dL (-61.0, 4.0) versus -1.0 mg/dL (-16.0, 17.0) in probands without GC (p = 0.0054). Probands with and without GC selected sharing strategies for 65.3% and 40.3% of FDRs, respectively (p < 0.0001). Similarly, 27.1% of FDRs of probands with GC completed cascade testing, while 12.0% of FDRs of probands without GC completed testing (p = 0.0043). Direct contact was selected for 47 relatives in total and completed for 39, leading to the detection of 18 relatives with FH. Proband GC was associated with improved medical outcomes and increased FDR cascade testing. Direct contact effectively identified FH cases for the subset who participated.

Genetic mechanisms underlying arrhythmogenic mitral valve prolapse: Current and future perspectives.

Mitral valve prolapse (MVP) is a heart valve disease that is often familial, affecting 2%-3% of the general population. MVP with or without mitral regurgitation can be associated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). Research on familial MVP has specifically focused on genetic factors, which may explain the heritable component of the disease estimated to be present in 20%-35%. Furthermore, the structural and electrophysiological substrates underlying SCD/ventricular arrhythmia risk in MVP have been studied postmortem and in the electrophysiology laboratory, respectively. Understanding how familial MVP and rhythm disorders are related may help patients with MVP by individualizing risk and working to develop effective management strategies. This contemporary, state-of-the-art, expert review focuses on genetic factors and familial components that underlie MVP and arrhythmia and encapsulates clinical, genetic, and electrophysiological issues that should be the objectives of future research.

Impact of a Population Genomic Screening Program on Health Behaviors Related to Familial Hypercholesterolemia Risk Reduction.

BACKGROUND: Limited information is available regarding clinician and participant behaviors after disclosure of genomic risk variants for familial hypercholesterolemia (FH) from a population genomic screening program. METHODS: We conducted a retrospective cohort study of MyCode participants with an FH risk variant beginning 2 years before disclosure until January 16, 2019. We analyzed lipid-lowering prescriptions (clinician behavior), medication adherence (participant behavior), and LDL (low-density lipoprotein) cholesterol levels (health outcome impact) pre- and post-disclosure. Data were collected from electronic health records and claims. RESULTS: The cohort included 96 participants of mean age 57 (22-90) years with median follow-up of 14 (range, 3-39) months. Most (90%) had a hypercholesterolemia diagnosis but no specific FH diagnosis before disclosure; 29% had an FH diagnosis post-disclosure. After disclosure, clinicians made 36 prescription changes in 38% of participants, mostly in participants who did not achieve LDL cholesterol goals pre-disclosure (81%). However, clinicians wrote prescriptions for fewer participants post-disclosure (71/96, 74.0%) compared with pre-disclosure (81/96, 84.4%); side effects were documented for most discontinued prescriptions (23/25, 92%). Among the 16 participants with claims data, medication adherence improved (proportion of days covered pre-disclosure of 70% [SD, 24.7%] to post-disclosure of 79.1% [SD, 27.3%]; P=0.05). Among the 52 (54%) participants with LDL cholesterol values both before and after disclosure, average LDL cholesterol decreased from 147 to 132 mg/dL (P=0.003). CONCLUSIONS: Despite disclosure of an FH risk variant, nonprescribing and nonadherence to lipid-lowering therapy remained high. However, when clinicians intensified medication regimens and participants adhered to medications, lipid levels decreased.