High-throughput discovery of trafficking-deficient variants in the cardiac potassium channel KV11.1

Kozek, Krystian A.; Glazer, Andrew M.; Ng, Chai Ann; Blackwell, Daniel J.; Egly, Christian; Vanags, Loren R.; Blair, Marcia; Mitchell, Devyn W.; Matreyek, Kenneth A.; Fowler, Douglas M.; Knollmann, Björn C.; Vandenberg, Jamie I.; Roden, Dan M.; Kroncke, Brett M.

doi:10.1016/j.hrthm.2020.05.041

Cited by 45 publications

(58 citation statements)

References 34 publications

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“…This assay has the potential to sample all possible amino acids substitution in KCNH2 variants in an unbiased manner, providing a database for patients and clinicians to identify the effect of a previously uncharacterized mutation on patient disease propensity. 214 Another strategy put forward was to use high-throughput patch-clamp together with surface enzyme-linked immunosorbent assays, which allowed to distinguish between KCNH2 benign, dominant-negative, or haploinsufficient variants, helping with KCNH2 variant classification. 215 Additionally, to test specific treatments for potential variants, pharmacological or temperature strategies were used in combination with high-throughput platforms and showed the enormous potential of these new methods to determine a patient-specific therapy treatment.…”

Section: Novel Strategies To Study Ion Channel Dysfunction and Drug-specific Therapies In Lqt1 Lqt2 And Lqt3 Syndromesmentioning

confidence: 99%

Long QT syndrome – Bench to bedside

Ponce-Balbuena

Deschênes

2021

Heart Rhythm O2

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Long QT syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval and T-wave irregularities on the surface electrocardiogram. It is commonly associated with syncope, seizures, susceptibility to torsades de pointes, and risk for sudden death. LQTS is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. The availability of therapy for this lethal disease emphasizes the importance of early and accurate diagnosis. Additionally, understanding of the molecular mechanisms underlying LQTS could help to optimize genotype-specific treatments to prevent deaths in LQTS patients. In this review, we briefly summarize current knowledge regarding molecular underpinning of LQTS, in particular focusing on LQT1, LQT2, and LQT3, and discuss novel strategies to study ion channel dysfunction and drug-specific therapies in LQT1, LQT2, and LQT3 syndromes.

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Section: Novel Strategies To Study Ion Channel Dysfunction and Drug-specific Therapies In Lqt1 Lqt2 And Lqt3 Syndromesmentioning

confidence: 99%

Long QT syndrome – Bench to bedside

Ponce-Balbuena

Deschênes

2021

Heart Rhythm O2

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“…In vitro screening assays have established that the loss of K v 11.1 function leads to familial LQTS type 2 (LQTS2). 21 , 22 , 23 These same assays routinely assess the modulation of K v 11.1 by drug candidates, which block a strong predictor of cardiac toxicity. 24 KCNH2 variants have been identified in SUDEP patients, including both rare pathogenic and common variants although statistically significant enrichment has not been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Loss‐of‐function variants in K_v11.1 cardiac channels as a biomarker for SUDEP

Soh

Bagnall

Bennett

et al. 2021

Ann Clin Transl Neurol

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Objective: To compare the frequency and impact on the channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss-offunction KCNH2 variants as predictive biomarkers of SUDEP risk. Methods: We searched for KCNH2 variants with a minor allele frequency of <5%. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified. Results: KCNH2 variants were found in 11.1% (10/90) of SUDEP individuals compared to 6.0% (20/332) of epilepsy controls (p = 0.11). Loss-offunction KCNH2 variants, defined as causing >20% reduction in maximal amplitude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about threefold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2%; 2/90) and epilepsy control (2.7%; 9/332) cohorts (p > 0.99). Rare KCNH2 variants (<1% allele frequency) associated with greater loss of function and an~11-fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis. Interpretation: These data show that loss-of-function KCNH2 variants are enriched in SUDEP patients when compared to an epilepsy population older than 50 years, suggesting that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss-of-function KCNH2 variants that could act as biomarkers of an individual's SUDEP risk.

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“…6,9,33 Based on in vitro functional testing and recently published hotspot criteria, 19 we were able to reclassify 12 of 52 examined variants. Future analyses studying even larger cohorts, independently or combined with high-throughput in vitro characterization 6,34 promise to further discern the disease risk of individual ultra-rare variants.…”

Section: Discussionmentioning

confidence: 99%

Arrhythmia variant associations and reclassifications in the eMERGE-III sequencing study

Am¹,

Davogustto²,

Cm³

et al. 2021

Preprint

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In 21,846 eMERGE-III participants, sequencing 10 arrhythmia syndrome disease genes identified 123 individuals with pathogenic or likely pathogenic (P/LP) variants. Compared to non-carriers, P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records (EHRs). Fifty one participants had variant results returned. Eighteen of these 51 participants had inherited arrhythmia syndrome diagnoses (primarily long QT syndrome), and 11/18 of these diagnoses were made only after variant results were returned. After in vitro functional evaluation of 50 variants of uncertain significance (VUS), we reclassified 11 variants: 3 to likely benign and 8 to P/LP. As large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, EHR phenotypes, and in vitro functional studies.

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High-throughput discovery of trafficking-deficient variants in the cardiac potassium channel KV11.1

Cited by 45 publications

References 34 publications

Long QT syndrome – Bench to bedside

Long QT syndrome – Bench to bedside

Loss‐of‐function variants in K_v11.1 cardiac channels as a biomarker for SUDEP

Arrhythmia variant associations and reclassifications in the eMERGE-III sequencing study

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High-throughput discovery of trafficking-deficient variants in the cardiac potassium channel KV11.1

Cited by 45 publications

References 34 publications

Long QT syndrome – Bench to bedside

Long QT syndrome – Bench to bedside

Loss‐of‐function variants in Kv11.1 cardiac channels as a biomarker for SUDEP

Arrhythmia variant associations and reclassifications in the eMERGE-III sequencing study

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Resources

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Loss‐of‐function variants in K_v11.1 cardiac channels as a biomarker for SUDEP