Identification of Undetected Monogenic Cardiovascular Disorders

Abdulrahim, Jawan; Kwee, Lydia Coulter; Alenezi, Fawaz; Sun, Albert Y.; Baras, Aris; Ajayi, Teminioluwa; Henao, Ricardo; Holley, Christopher L.; McGarrah, Robert W.; Daubert, James P.; Truby, Lauren K.; Vemulapalli, Sreekanth; Wang, Andrew; Khouri, Michel G.; Shah, Svati H.

doi:10.1016/j.jacc.2020.06.037

Cited by 18 publications

(14 citation statements)

References 36 publications

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“…A total of 8574 individuals in the Catheterization Genetics (CATHGEN) biorepository 15 had exome sequencing passing quality control measures as previously detailed. 4 Seven hundred seven P/LP variants, variants of uncertain significance (VUS), or novel null/truncating variants in 52 arrhythmia-related genes were identified in 948 individuals (11.1%). Of these, 58 variants were P/LP based on American College of Genetics and Genomics/Association for Molecular Pathology criteria evaluation, residing in 12 genes associated with 5 arrhythmogenic disorders (arrhythmogenic right ventricular cardiomyopathy [ARVC], Brugada syndrome [BrS], hypertrophic cardiomyopathy [HCM], LMNA -related cardiomyopathy, and long QT syndrome [LQTS]) in 79 individuals (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…Structured and unstructured EHR-based phenotyping was conducted. Demographic and clinical characteristics at the time of CATHGEN enrollment for all P/LP variant carriers, VUS carriers, and variant-negative individuals (ie, those not carrying P/LP variants in any monogenic cardiovascular disease gene as previously defined 4 Table S1) are presented in Table 1. The median (interquartile range) length of follow-up among all variant carriers and matched noncarriers was 15 (9–25) years and 15 (7–23) years, respectively ( P =0.5).…”

Section: Resultsmentioning

confidence: 99%

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Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics

Nafissi¹,

Abdulrahim

Kwee³

et al. 2022

Circ: Genomic and Precision Medicine

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BACKGROUND: Inherited primary arrhythmia syndromes and arrhythmogenic cardiomyopathies can lead to sudden cardiac arrest in otherwise healthy individuals. The burden and expression of these diseases in a real-world, well-phenotyped cardiovascular population is not well understood. METHODS: Whole exome sequencing was performed on 8574 individuals from the CATHGEN cohort. Variants in 55 arrhythmia-related genes (associated with 8 disorders) were identified and assessed for pathogenicity based on American College of Genetics and Genomics/Association for Molecular Pathology criteria. Individuals carrying pathogenic/likely pathogenic (P/LP) variants were grouped by arrhythmogenic disorder and matched 1:5 to noncarrier controls based on age, sex, and genetic ancestry. Long-term phenotypic data were annotated through deep electronic health record review. RESULTS: Fifty-eight P/LP variants were found in 79 individuals in 12 genes associated with 5 arrhythmogenic disorders (arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, hypertrophic cardiomyopathy, LMNA -related cardiomyopathy, and long QT syndrome). The penetrance of these P/LP variants in this cardiovascular cohort was 33%, 0%, 28%, 83%, and 4%, respectively. Carriers of P/LP variants associated with arrhythmogenic disorders showed significant differences in ECG, imaging, and clinical phenotypes compared with noncarriers, but displayed no difference in survival. Carriers of novel truncating variants in FLNC, MYBPC3, and MYH7 also developed relevant arrhythmogenic cardiomyopathy phenotypes. CONCLUSIONS: In a real-world cardiovascular cohort, P/LP variants in arrhythmia-related genes were relatively common (1:108 prevalence) and most penetrant in LMNA . While hypertrophic cardiomyopathy P/LP variant carriers showed significant differences in clinical outcomes compared with noncarriers, carriers of P/LP variants associated with other arrhythmogenic disorders displayed only ECG differences.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics

Nafissi¹,

Abdulrahim

Kwee³

et al. 2022

Circ: Genomic and Precision Medicine

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“…The mechanistic focus should help to address rare cardiovascular indications, for which the return on investment has often been insufficient motivation to develop a drug from concept to bedside. In aggregate, rare cardiovascular diseases are estimated to affect up to 3% of the population 7 , 8 , making the lack of drug development for this population a major health problem. Rare diseases often have monogenic aetiologies 7 , 8 , for which the clear genetics make them well suited to new computational and experimental drug discovery technologies.…”

Section: Introductionmentioning

confidence: 99%

“…In aggregate, rare cardiovascular diseases are estimated to affect up to 3% of the population 7 , 8 , making the lack of drug development for this population a major health problem. Rare diseases often have monogenic aetiologies 7 , 8 , for which the clear genetics make them well suited to new computational and experimental drug discovery technologies.…”

Section: Introductionmentioning

confidence: 99%

Repurposing drugs to treat cardiovascular disease in the era of precision medicine

et al. 2022

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Drug repurposing is the use of a given therapeutic agent for indications other than that for which it was originally designed or intended. The concept is appealing because of potentially lower development costs and shorter timelines than are needed to produce a new drug. To date, drug repurposing for cardiovascular indications has been opportunistic and driven by knowledge of disease mechanisms or serendipitous observation rather than by systematic endeavours to match an existing drug to a new indication. Innovations in two areas of personalized medicine — computational approaches to associate drug effects with disease signatures and predictive model systems to screen drugs for disease-modifying activities — support efforts that together create an efficient pipeline to systematically repurpose drugs to treat cardiovascular disease. Furthermore, new experimental strategies that guide the medicinal chemistry re-engineering of drugs could improve repurposing efforts by tailoring a medicine to its new indication. In this Review, we summarize the historical approach to repurposing and discuss the technological advances that have created a new landscape of opportunities.

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“… 1 Genetic testing and advanced imaging have shown that the prevalence of IC is higher than previously thought (eg, HCM prevalence of 1:200–300 versus 1:500). 2 , 3 , 4 Yet, ICs are still relatively rare and general cardiologists have little experience in diagnosing and managing individuals with these conditions and screening their family members. Consequently, experts and international societies, such as the American Heart Association, have recognized the need for dedicated clinics for IC.…”

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confidence: 99%

Establishment of a Dedicated Inherited Cardiomyopathy Clinic: From Challenges to Improved Patients’ Outcome

Smith

Thompson

Burke-Martindale

et al. 2022

JAHA

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Background Inherited cardiomyopathies (ICs) are relatively rare. General cardiologists have little experience in diagnosing and managing these conditions. International societies have recognized the need for dedicated IC clinics. However, only few reports on such clinics are available. Methods and Results Clinical data of patients referred to our clinic during its first 2 years for a personal or family history of (possible) IC were analyzed. A total of 207 patients from 196 families were seen; 13% of probands had their diagnosis changed. Diagnosis was most commonly altered in patients referred for possible arrhythmogenic dominant right ventricular cardiomyopathy (62.5%). A total of 90% of probands had genetic testing, of whom 27.3% harbored a likely pathogenic or pathogenic variant. Of patients with confirmed hypertrophic cardiomyopathy, 31 (28.7%) were treated for left ventricular outflow tract obstruction, including septal reduction in 13. Patients with either hypertrophic cardiomyopathy or left ventricular noncompaction and a history of atrial fibrillation were started on oral anticoagulation. Oral anticoagulation was also discussed with all patients with hypertrophic cardiomyopathy and apical aneurysm. Patients with a definite diagnosis of arrhythmogenic dominant right ventricular cardiomyopathy were started on β‐blockers and given restrictive exercise prescriptions. A total of 17 patients with hypertrophic cardiomyopathy and 5 patients with likely pathogenic or likely variants in arrhythmogenic genes received primary prevention implantable cardioverter‐defibrillators. No implantable cardioverter‐defibrillators were warranted for arrhythmogenic dominant right ventricular cardiomyopathy. A total of 76 family members from 24 families had cascade screening, 32 of whom carried the familial variant. A total of 21 members from 13 gene‐elusive families were evaluated by clinical screening, 3 of whom had positive screening. Conclusions Specialized IC clinics may improve diagnosis, management, and outcomes of patients with (possible) IC and their family members.

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Identification of Undetected Monogenic Cardiovascular Disorders

Cited by 18 publications

References 36 publications

Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics

Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics

Repurposing drugs to treat cardiovascular disease in the era of precision medicine

Establishment of a Dedicated Inherited Cardiomyopathy Clinic: From Challenges to Improved Patients’ Outcome

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