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Circulation Jul 2020Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect...
BACKGROUND
Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.
METHODS
We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.
RESULTS
Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).
CONCLUSIONS
This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
Topics: Adolescent; Adult; Age of Onset; Alleles; Case-Control Studies; Electrocardiography; Genetic Association Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Long QT Syndrome; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide; Prognosis; Severity of Illness Index; Young Adult
PubMed: 32429735
DOI: 10.1161/CIRCULATIONAHA.120.045956 -
Journal of Pharmacokinetics and... Apr 2021
Topics: Dose-Response Relationship, Drug; Drug Approval; Drug Recalls; Electrocardiography; Humans; Long QT Syndrome; Models, Biological; Software; Terfenadine
PubMed: 33826074
DOI: 10.1007/s10928-021-09754-z -
Cardiology in the Young Aug 2020Cardio-facio-cutaneous syndrome is a genetic anomaly characterised by craniofacial dysmorphia, developmental retardation, skin lesions, mental retardation/learning...
Cardio-facio-cutaneous syndrome is a genetic anomaly characterised by craniofacial dysmorphia, developmental retardation, skin lesions, mental retardation/learning disability, and cardiac malformations. Cardio-facio-cutaneous syndrome rarely causes arrhythmias and has not been previously associated with long QT in the literature. With this report, it was aimed to draw attention to a different presentation of the long QT syndrome.
Topics: Ectodermal Dysplasia; Facies; Failure to Thrive; Heart Defects, Congenital; Humans; Long QT Syndrome
PubMed: 32635955
DOI: 10.1017/S1047951120001808 -
Circulation Dec 2020
Topics: Arrhythmias, Cardiac; Humans; Long QT Syndrome
PubMed: 33347325
DOI: 10.1161/CIRCULATIONAHA.120.051434 -
Journal of the American College of... Dec 2020
Topics: Death, Sudden, Cardiac; Echocardiography; Humans; Long QT Syndrome; Risk Assessment
PubMed: 33303073
DOI: 10.1016/j.jacc.2020.10.043 -
BMC Pediatrics Mar 2020Syncope is a common and often benign disorder presenting at the pediatric emergency department. Long-QT syndrome may be presented with syncope, ventricular arrhythmias...
BACKGROUND
Syncope is a common and often benign disorder presenting at the pediatric emergency department. Long-QT syndrome may be presented with syncope, ventricular arrhythmias or sudden death and is vital to exclude as an underlying cause in children presented with syncope. Few studies have assessed QTc in relation to body posture in children. In this study, we assessed the QTc interval while laying down and during active standing in children with known long-QT syndrome compared to healthy controls.
METHODS
Children aged 1-18 years with long-QT syndrome (N = 17) matched to two healthy controls (N = 34) were included in this case-control study. The ECG standing was performed immediately after the ECG in the supine position. The QTc interval and QTc-difference by changing the body position were calculated.
RESULTS
All children with long-QT syndrome were treated with propranolol. QTc was prolonged among long-QT syndrome children while lying down and when standing up, compared to controls. A prolongation of QTc appeared when standing up for both cases and controls. There was no significant difference in QTc increase between the groups. A QTc over 440 ms was observed among four cases lying down and in eight cases while standing, but not in any of the controls. The standing test with a cut-off of 440 ms showed a sensitivity of 47% and a specificity of 100% for case-status in our study.
CONCLUSION
QTc measured on ECG when rapidly rising up is prolonged in both healthy and LQTS children. More importantly, it prolongs more in children with LQTS and increases in pathological levels.
Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Electrocardiography; Female; Humans; Infant; Long QT Syndrome; Male; Pediatrics; Posture; Syncope
PubMed: 32138709
DOI: 10.1186/s12887-020-1959-8 -
Fetal and Pediatric Pathology Dec 2022While much is known about the channelopathy disorder Long QT Syndrome (LQTS), the histopathological findings and their implications on the disease have remained largely... (Review)
Review
While much is known about the channelopathy disorder Long QT Syndrome (LQTS), the histopathological findings and their implications on the disease have remained largely unexplored to date. In this review, we discuss the background of LQTS and highlight the importance of histological findings in the absence of genetic markers or when genetic testing is unavailable. Three pediatric cases of LQTS were identified, evaluated histologically, and compared to two adult cases. Histological examination of three pediatric LQTS patients demonstrated fibrotic alterations to the cardiac conduction system with markedly decreased conductive tissue density and volume. Both adult cases revealed fibrosis with similar reductions in tissue volume. When diagnostic methods such as genetic testing are unavailable, histopathology offers clinicians an alternative tool for postmortem diagnosis of LQTS when considered alongside clinical presentation. Confirmation of diagnosis in a proband can prevent the death of relatives in hereditary LQTS.
Topics: Adult; Humans; Child; Electrocardiography; Long QT Syndrome; Genetic Testing
PubMed: 34766536
DOI: 10.1080/15513815.2021.2002988 -
Journal of the American Heart... Jul 2021Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life-threatening events in women with either type 1 or type 2 long QT. Methods...
Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life-threatening events in women with either type 1 or type 2 long QT. Methods and Results The prognostic model was derived from the Rochester Long QT Syndrome Registry, comprising 767 women with type 1 long QT (n=404) and type 2 long QT (n=363) from age 15 through 60 years. The risk prediction model included the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and β-blocker therapy. A model was developed with the end point of CEs (syncope, aborted cardiac arrest, or long QT syndrome-related sudden cardiac death), and was applied with the end point of life-threatening events (aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shocks). External validation was performed with data from the Mayo Clinic Genetic Heart Rhythm Clinic (N=467; type 1 long QT [n=286] and type 2 long QT [n=181]). The cumulative follow-up duration among the 767 enrolled women was 22 243 patient-years, during which 323 patients (42%) experienced ≥1 CE. Based on genotype-phenotype data, we identified 3 risk groups with 10-year projected rates of CEs ranging from 15%, 29%, to 51%. The corresponding 10-year projected rates of life-threatening events were 2%, 5%, and 14%. C statistics for the prediction model for the 2 respective end points were 0.68 (95% CI 0.65-0.71) and 0.71 (95% CI 0.66-0.76). Corresponding C statistics for the model in the external validation Mayo Clinic cohort were 0.65 (95% CI 0.60-0.70) and 0.77 (95% CI 0.70-0.84). Conclusions This is the first risk prediction model that provides absolute risk estimates for CEs and life-threatening events in women with type 1 or type 2 long QT based on personalized genotype-phenotype data. The projected risk estimates can be used to guide female-specific management in long QT syndrome.
Topics: Adolescent; Adult; Death, Sudden, Cardiac; Electrocardiography; Female; Genotype; Humans; Incidence; Long QT Syndrome; Middle Aged; Phenotype; Registries; Risk Assessment; Risk Factors; Survival Rate; United States; Young Adult
PubMed: 34238014
DOI: 10.1161/JAHA.121.021088 -
Current Opinion in Cardiology May 2023To summarize and critically assess the contribution of genetics to the Long QT Syndrome (LQTS), with specific reference to the unraveling of its underlying mechanisms... (Review)
Review
PURPOSE OF REVIEW
To summarize and critically assess the contribution of genetics to the Long QT Syndrome (LQTS), with specific reference to the unraveling of its underlying mechanisms and to its impact on clinical practice.
RECENT FINDINGS
The evolution towards our current approach to therapy for LQTS patients is examined in terms of risk stratification, gene-specific management, and assessment of the clinical impact that genetic modifiers may have in modulating the natural history of the patients. Glimpses are provided on the newest multidisciplinary approaches to study disease mechanisms, test new candidate drugs and identify precision treatments.
SUMMARY
It is undeniable that genetics has revolutionized our mechanistic understanding of cardiac channelopathies. Its impact has been enormous but, curiously, the way LQTS patients are being treated today is largely the same that was used in the pregenetic era, even though management has been refined and gene-specific differences allow a more individually tailored antiarrhythmic protection. The synergy of genetic findings with modern in vitro and in silico tools may expand precision treatments; however, they will need to prove more effective than the current therapeutic approaches and equally safe.
Topics: Humans; Long QT Syndrome; Arrhythmias, Cardiac; Anti-Arrhythmia Agents
PubMed: 36789771
DOI: 10.1097/HCO.0000000000001027 -
Circulation. Arrhythmia and... Feb 2024Genetic testing has become standard of care for patients with long QT syndrome (LQTS), providing diagnostic, prognostic, and therapeutic information for both probands... (Review)
Review
Genetic testing has become standard of care for patients with long QT syndrome (LQTS), providing diagnostic, prognostic, and therapeutic information for both probands and their family members. However, up to a quarter of patients with LQTS do not have identifiable Mendelian pathogenic variants in the currently known LQTS-associated genes. This absence of genetic confirmation, intriguingly, does not lessen the severity of LQTS, with the prognosis in these gene-elusive patients with unequivocal LQTS mirroring genotype-positive patients in the limited data available. Such a conundrum instigates an exploration into the causes of corrected QT interval (QTc) prolongation in these cases, unveiling a broad spectrum of potential scenarios and mechanisms. These include multiple environmental influences on QTc prolongation, exercise-induced repolarization abnormalities, and the profound implications of the constantly evolving nature of genetic testing and variant interpretation. In addition, the rapid advances in genetics have the potential to uncover new causal genes, and polygenic risk factors may aid in the diagnosis of high-risk patients. Navigating this multifaceted landscape requires a systematic approach and expert knowledge, integrating the dynamic nature of genetics and patient-specific influences for accurate diagnosis, management, and counseling of patients. The role of a subspecialized expert cardiogenetic clinic is paramount in evaluation to navigate this complexity. Amid these intricate aspects, this review outlines potential causes of gene-elusive LQTS. It also provides an outline for the evaluation of patients with negative and inconclusive genetic test results and underscores the need for ongoing adaptation and reassessment in our understanding of LQTS, as the complexities of gene-elusive LQTS are increasingly deciphered.
Topics: Humans; Electrocardiography; Long QT Syndrome; Genotype; Risk Factors; Genetic Testing
PubMed: 38264885
DOI: 10.1161/CIRCEP.123.012356