| 1. |
- Lahrouchi, Najim, et al.
(author)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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In: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Journal article (peer-reviewed)abstract
- 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 (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). 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 (P<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 (P<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.
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| 2. |
- Walsh, Roddy, et al.
(author)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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In: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Journal article (peer-reviewed)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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| 3. |
- Jansweijer, Joeri A., et al.
(author)
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Heritability in genetic heart disease : the role of genetic background
- 2019
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In: Open heart. - : BMJ Publishing Group Ltd. - 2053-3624. ; 6:1
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Journal article (peer-reviewed)abstract
- Background: Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or ‘modifier genes’. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins.Methods: We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy.Results: Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy.Conclusions: Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.
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| 4. |
- Cortez, Daniel, et al.
(author)
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ECG-derived spatial QRS-T angle is strongly associated with hypertrophic cardiomyopathy
- 2017
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In: Journal of Electrocardiology. - : Elsevier BV. - 0022-0736 .- 1532-8430. ; 50:2, s. 195-202
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Journal article (peer-reviewed)abstract
- Introduction: ECG-derived vectorcardiography (VCG) has diagnostic and prognostic value in various diseases. Hypertrophic cardiomyopathy (HCM), a genetic disease with unexplained left ventricular hypertrophy, is one of the most common causes of sudden cardiac death (SCD) in young persons. Genotype positive status is associated with increased risk of systolic dysfunction, heart failure, and (SCD). Herein, we aimed to determine the diagnostic utility of derived VCG parameters in a large cohort of genotyped HCM patients. Methods: Between 1997 and 2007, genetic testing was performed on 1053 unrelated patients with HCM. Of these, 967 had 12-lead ECGs suitable for computerized derivation of VCG parameters, including the spatial mean and peaks QRS-T angles, spatial ventricular gradient (SVG), spatial QRS, QT, and Tpeak-Tend (TpTe) intervals. ECGs were also evaluated using Seattle ECG criteria. Differences between HCM patients and healthy controls as well as between genotype positive versus genotype negative HCM patients were assessed. Results: Spatial peaks (129.3. ±. 26.4 vs.30.5. ±. 24.2 degrees) and spatial mean QRS-T angles (121.8. ±. 38.6 vs. 47.3. ±. 27.6 degrees) were significantly higher in patients with HCM than in controls (P. <. 0.001). The spatial peaks and mean QRS-T angles identified 94% and 84% of HCM patients, respectively, while Seattle criteria identified 70.7% of patients (P. <. 0.001). Genotype positive patients had higher spatial mean QRS-T angles, spatial TpTe (P. <. 0.001 respectively), spatial peaks QRS-T angles (P. =0.017) and lower SVG (P. <. 0.001) than genotype negative patients. Conclusions: ECG-derived spatial QRS-T angles can differentiate patients with HCM from controls and could provide a better tool than traditional Seattle criteria. Clinical usefulness of VCG to differentiate genotype-negative from genotype-positive patients has yet to be established.
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| 5. |
- Cortez, Daniel, et al.
(author)
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Vectorcardiography identifies patients with electrocardiographically concealed long QT syndrome
- 2017
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In: Heart Rhythm. - : Elsevier BV. - 1547-5271. ; 14:6, s. 894-899
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Journal article (peer-reviewed)abstract
- Background Long QT syndrome (LQTS) and genotypic subtypes are associated with distinctive T-wave patterns, arrhythmogenic triggers, and corrected QT (QTc) interval risk associations. Twenty percent of patients with LQTS have normal QTc values, defined as electrographically concealed LQTS (ecLQTS). Vectorcardiography (VCG) has value for sudden cardiac death risk assessment. Objective The purpose of this study was to determine the use of VCG to identify patients with ecLQTS. Methods We performed a retrospective analysis in patients with ecLQTS with resting QTc values <440 ms. Computerized derivation of the spatial mean and peak QRS-T angles, QTpeak, Tpeak-Tend (angle between QRS and T-wave peak amplitudes in 3-dimensional space), and T-wave eigenvalues (TwEVs; amplitudes [in microvolts] for each of the first 4 TwEVs were derived from the 12-lead electrocardiogram) was performed. The results were compared with those for healthy controls. Intergenotype differences were analyzed. Results Of 610 patients with LQTS, 169 patients (28%) had ecLQTS (86 (51%) men; mean age 22 ± 16 years; mean QTc interval 422 ± 14 ms). There were 519 healthy controls (44% men; mean age 19.8 ± 13.8 years) with a mean QTc interval of 426 ± 28 ms. Among VCG parameters, QTpeak and TwEVs significantly differentiated patients with ecLQTS from controls (P ≤.01 for each) as well as differentiated KCNQ1-encoded type 1 LQTS (ecLQT1), KCNH2-encoded type 2 LQTS (ecLQT2), and SCN5A-encoded type 3 LQTS (ecLQT3) from controls (P <.01). ecLQT3 was differentiated from controls and ecLQT1 and ecLQT2 by the fourth TwEV (P <.01 for each). The fourth TwEV differentiated symptomatic patients with ecLQTS from asymptomatic patients with ecLQTS (P <.01). Conclusion ecLQTS can be distinguished from controls using QTpeak. ecLQT3 was best differentiated by the fourth TwEV. VCG may facilitate familial diagnostic anticipation of LQTS status before the completion of mutation-specific genetic testing even with normal resting QTc values.
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| 6. |
- Rutten, Martijn G. S., et al.
(author)
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Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia
- 2023
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In: Cancer & Metabolism. - : Springer Nature. - 2049-3002. ; 11:1
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Journal article (peer-reviewed)abstract
- BackgroundGlycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia.MethodsHepatocyte-specific G6pc knockout (L-G6pc−/−) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity.ResultsHepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged.ConclusionsIn conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.
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