Cost-Effectiveness of Genetic Studies in Inherited Heart Diseases

Sabater-Molina, María; García-Molina, Esperanza; Tovar, I.; Ruíz-Espejo, Francisco; Gimeno, Juan R.; Valdés, Mariano

doi:10.4081/cardiogenetics.2013.e5

Cited by 6 publications

(12 citation statements)

References 9 publications

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“…S7; Supplemental Table S4c) observed by both automated and manual patch clamp recording. Notable is the behavior of P197L, a rare variant originally described in a study of cost effectiveness of genetic testing for heritable cardiac disorders including LQTS, 34 but also discovered incidentally in a breast cancer cohort undergoing exome sequencing. 35 This variant exhibits a moderate gain-of-function (145% of WT current) that is inconsistent with a mutation causing LQTS.…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance

Vanoye

Desai

Fabre

et al. 2018

Circ: Genomic and Precision Medicine

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Background The explosive growth in known human gene variation presents enormous challenges to current approaches for variant classification that have implications for diagnosis and treatment of many genetic diseases. For disorders caused by mutations in cardiac ion channels as in congenital arrhythmia syndromes, in vitro electrophysiological evidence has high value in discriminating pathogenic from benign variants, but these data are often lacking because assays are cost-, time- and labor-intensive. Methods We implemented a strategy for performing high throughput, functional evaluations of ion channel variants that repurposed an automated electrophysiological recording platform developed previously for drug discovery. Results We demonstrated success of this approach by evaluating 78 variants in KCNQ1, a major gene involved in genetic disorders of cardiac arrhythmia susceptibility. We benchmarked our results with traditional electrophysiological approaches and observed a high level of concordance. This strategy also enabled studies of dominant-negative behavior of variants exhibiting severe loss-of-function. Overall, our results provided functional data useful for reclassifying more than 65% of the studied KCNQ1 variants. Conclusions Our results illustrate an efficient and high throughput paradigm linking genotype to function for a human cardiac ion channel that will enable data-driven classification of large numbers of variants and create new opportunities for precision medicine.

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Section: Resultsmentioning

confidence: 99%

High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance

Vanoye

Desai

Fabre

et al. 2018

Circ: Genomic and Precision Medicine

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“…25 Although the cost-effectiveness of genetic testing in DCM has not yet been evaluated, studies on the cost-effectiveness of genetic testing in hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and long QT syndrome indicate an overall benefit over screening via cardiac surveillance. 26,27 …”

Section: Discussionmentioning

confidence: 99%

Differences in Presentation and Outcomes Between Children With Familial Dilated Cardiomyopathy and Children With Idiopathic Dilated Cardiomyopathy

Rusconi

Wilkinson

Sleeper

et al. 2017

Circ: Heart Failure

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Background Research comparing the survival of children with familial dilated cardiomyopathy (FDCM) to that of children with idiopathic dilated cardiomyopathy (IDCM) has produced conflicting results. Methods and Results We analyzed data from children with FDCM or IDCM using the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry. Compared to children with IDCM (n=647), children with FDCM (n=223) were older (mean 6.2 vs. 4.5 years, P <0.001), less often had heart failure (64% vs. 78%, P <0.001), had less-depressed mean left ventricular (LV) fractional shortening z-scores (−7.85 ± 3.98 vs. −9.06 ± 3.89, P <0.001) and lower end-diastolic dimension z-scores (4.12 ± 2.61 vs. 4.91 ± 2.57, P <0.001) at diagnosis. The cumulative incidence of death was lower for patients with FDCM compared with IDCM (P=0.04; hazard ratio 0.64, P=0.06) but no difference in risk of transplant or the combined death or transplant outcome. There was no difference in the proportion of children with echocardiographic normalization at three years of follow-up (FDCM, 30% vs. IDCM, 26%; P=0.33). Multivariable analysis showed no difference in outcomes between FDCM and IDCM but for both groups older age, congestive heart failure (CHF) and increased LV end-systolic dimension z-score at diagnosis were independently associated with an increased risk of death or heart transplantation (all Ps <0.001). Conclusions There was no survival difference between FDCM and IDCM after adjustment for other factors. Older age, CHF, and greater LV dilation at diagnosis were independently associated with increased risk of the combined endpoint of death or transplantation. Clinical Trial Registration https://clinicaltrials.gov; NCT00005391

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“…S5; Supplemental Table S2c). Notable is the behavior of P197L, a rare variant originally described in a study of cost effectiveness of genetic testing for heritable cardiac disorders including LQTS, 31 but also discovered incidentally in a breast cancer cohort undergoing exome sequencing. 32 This variant exhibits a moderate gain-of-function (145% of WT current) that is inconsistent with a mutation causing LQTS.…”

Section: Functional Properties Of Kcnq1 Variants Of Unknown Significancementioning

confidence: 99%

High Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance

Vanoye¹,

Fabre²,

Potet³

et al. 2017

Preprint

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Cost-Effectiveness of Genetic Studies in Inherited Heart Diseases

Cited by 6 publications

References 9 publications

High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance

High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance

Differences in Presentation and Outcomes Between Children With Familial Dilated Cardiomyopathy and Children With Idiopathic Dilated Cardiomyopathy

High Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance

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