Response by Crotti et al to Letter Regarding Article, “Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3′ Untranslated Region of KCNQ1?”

Crotti, Lia; Lahtinen, Annukka M.; Spazzolini, Carla; Mastantuono, Elisa; Monti, Maria Cristina; Morassutto, Caterina; Parati, Gianfranco; Heradien, Marshall; Goosen, Althea; Lichtner, Peter; Meitinger, Thomas; Brink, Paul A.; Kontula, Kimmo; Swan, Heikki; Schwartz, Peter J.

doi:10.1161/circgenetics.116.001635

Cited by 15 publications

(8 citation statements)

References 7 publications

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“…The rs8234 variant in the 3 ′ UTR of KCNQ1 is of interest also because there is evidence that it is a functional SNP. Rs8234 has been shown experimentally to influence the expression level of KCNQ1 with the A allele being associated with higher expression than the G allele by luciferase reporter assays as well as by using the clinical phenotype of QT length (Amin et al 2012) although the association with QT has not been replicated (Crotti et al 2016). In our sample, the A allele was jointly associated with reduced processing speed, reduced white matter FA and higher risk for schizophrenia.…”

Section: Discussionmentioning

confidence: 65%

Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia

Bruce

Kochunov

Paciga

et al. 2017

Genes Brain and Behavior

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Patients with schizophrenia show decreased processing speed on neuropsychological testing and decreased white matter integrity as measured by diffusion tensor imaging, two traits shown to be both heritable and genetically associated indicating that there may be genes that influence both traits as well as schizophrenia disease risk. The potassium channel gene family is a reasonable candidate to harbor such a gene given the prominent role potassium channels play in the central nervous system in signal transduction, particularly in myelinated axons. We genotyped members of the large potassium channel gene family focusing on putatively functional single nucleotide polymorphisms (SNPs) in a population of 363 controls, 194 patients with schizophrenia spectrum disorder, and 28 patients with affective disorders with psychotic features who completed imaging and neuropsychological testing. We then performed three association analyses using three phenotypes- processing speed, whole-brain white matter fractional anisotropy, and schizophrenia spectrum diagnosis. We extracted SNPs showing an association at a nominal P value of <0.05 with all three phenotypes in the expected direction: decreased processing speed, decreased fractional anisotropy, and increased risk of schizophrenia spectrum disorder. A single SNP, rs8234, in the 3′ untranslated region (UTR) of voltage-gated potassium channel subfamily Q member 1 (KCNQ1) was identified. Rs8234 has been shown to affect KCNQ1 expression levels, and KCNQ1 levels have been shown to affect neuronal action potentials. This exploratory analysis provides preliminary data suggesting that KCNQ1 may contribute to the shared risk for diminished processing speed, diminished white mater integrity, and increased risk of schizophrenia.

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Section: Discussionmentioning

confidence: 65%

Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia

Bruce

Kochunov

Paciga

et al. 2017

Genes Brain and Behavior

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“…Some genotype-positive patients never develop a clinically relevant disease, some remain asymptomatic (incomplete penetrance), and some show QTc prolongation without cardiac events, whereas others are severely affected and experience serious cardiac events at an early age (variable expressivity). 4,183 This variation may indicate the presence of significant environmental factors or genetic modifiers, such as common genetic variants of single nucleotide polymorphisms (SNPs) located in the same or a different gene, which can modulate the functional effect of LQTS mutations and therefore can either exacerbate or mitigate the final LQTS phenotype [184][185][186][187][188][189][190][191][192][193][194] (Table 4). SNPs can act either independent of or in concert with the LQTS-causing mutation.…”

Section: Lqts Genotype-phenotype Discordance and Single Nucleotide Polymorphismsmentioning

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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“…Extrapolation to the general population did not reveal that 3 0 -UTR variants in KCNQ1 impact the QT interval suggesting that this effect may only be relevant in the context of heterozygous KCNQ1 mutation. Attempts to replicate these findings in three LQT1 founder populations failed 26 possibly because of differences in genetic architecture of the 3 0 -UTR, different statistical approaches or the nature of the primary mutations. 27,28 Additional investigations are needed to determine the robustness of these findings.…”

Section: Genetic Modifiers Of Long Qt Syndromementioning

confidence: 99%

Modifier genes for sudden cardiac death

Schwartz

Crotti

George

2018

European Heart Journal

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Genetic conditions, even those associated with identical gene mutations, can present with variable clinical manifestations. One widely accepted explanation for this phenomenon is the existence of genetic factors capable of modifying the consequences of disease-causing mutations (modifier genes). Here, we address the concepts and principles by which genetic factors may be involved in modifying risk for cardiac arrhythmia, then discuss the current knowledge and interpretation of their contribution to clinical heterogeneity. We illustrate these concepts in the context of two important clinical conditions associated with risk for sudden cardiac death including a monogenic disorder (congenital long QT syndrome) in which the impact of modifier genes has been established, and a complex trait (life-threatening arrhythmias in acute myocardial infarction) for which the search for genetic modifiers of arrhythmic risk is more challenging. Advances in understanding the contribution of modifier genes to a higher or lower propensity towards sudden death should improve patient-specific risk stratification and be a major step towards precision medicine.

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Response by Crotti et al to Letter Regarding Article, “Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3′ Untranslated Region of KCNQ1?”

Cited by 15 publications

References 7 publications

Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia

Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia

Long QT syndrome – Bench to bedside

Modifier genes for sudden cardiac death

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