Syndactyly and long QT syndrome (CaV1.2 missense mutation G406R) is associated with hypertrophic cardiomyopathy

Lo-A-Njoe, Shirley M.; Wilde, Arthur A.M.; Erven, Lieselot van; Blom, Nico A.

doi:10.1016/j.hrthm.2005.08.024

Cited by 30 publications

(17 citation statements)

References 11 publications

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“…4C). The simulations are consistent with the observation that 100% of the TS mutation carrier exhibits QT interval prolongation (22,41,42).…”

Section: Resultssupporting

confidence: 88%

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L-type Ca²⁺ channel mutations and T-wave alternans: a model study

Zhu¹,

Clancy²

2007

American Journal of Physiology-Heart and Circulatory Physiology

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Zhu ZI, Clancy CE. L-type Ca 2ϩ channel mutations and T-wave alternans: a model study. Am J Physiol Heart Circ Physiol 293: H3480-H3489, 2007. First published October 12, 2007; doi:10.1152/ajpheart.00476.2007.-A number of mutations have been linked to diseases for which the underlying mechanisms are poorly understood. An example is Timothy Syndrome (TS), a multisystem disorder that includes severe cardiac arrhythmias. Here we employ theoretical simulations to examine the effects of a TS mutation in the L-type Ca 2ϩ channel on cardiac dynamics over multiple scales, from a gene mutation to protein, cell, tissue, and finally the ECG, to connect a defective Ca 2ϩ channel to arrhythmia susceptibility. Our results indicate that 1) the TS mutation disrupts the ratedependent dynamics in a single cardiac cell and promotes the development of alternans; 2) in coupled tissue, concordant alternans is observed at slower heart rates in mutant tissue than in normal tissue and, once initiated, rapidly degenerates into discordant alternans and conduction block; and 3) the ECG computed from mutant-simulated tissue exhibits prolonged QT intervals at physiological rates and with small increases in pacing rate, T-wave alternans, and alternating T-wave inversion. At the cellular level, enhanced Ca 2ϩ influx due to the TS mutation causes electrical instabilities. In tissue, the interplay between faulty Ca 2ϩ influx and steep action potential duration restitution causes arrhythmogenic discordant alternans. The prolongation of action potentials causes spatial dispersion of the Na ϩ channel excitability, leading to inhomogeneous conduction velocity and large action potential spatial gradients. Our model simulations are consistent with the ECG patterns from TS patients, which suggest that the TS mutation is sufficient to cause the clinical phenotype and allows for the revelation of the complex interactions of currents underlying it.modeling; Timothy Syndrome VOLTAGE-GATED ION CHANNELS underlie critical physiological processes like cardiac excitation, muscle contraction, and nerve impulses. In the last two decades, a number of genetic defects in ion channels have been identified and causally linked to a wide variety of clinical diseases, including cardiac arrhythmias, epilepsy, and disorders of muscle contraction. However, the question of exactly how a genetic mutation causes, or if it is sufficient to explain, the clinically observed disease state has been difficult to answer. This is largely due to limitations in the available investigative techniques that permit examination of derangements at individual scales, such as experiments to identify how specific mutations alter kinetic properties of channels but rarely provide information about the emergent effects of the mutations. It is precisely the emergent effects that result from nonlinear interactions within cells, between cells, and among various tissue components that cause disease. In the clinic, the ECG provides information about the organ level manifestation of disease but reveals ...

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“…4C). The simulations are consistent with the observation that 100% of the TS mutation carrier exhibits QT interval prolongation (22,41,42).…”

Section: Resultssupporting

confidence: 88%

“…In the clinical studies (22,41,42), extreme T-wave alternans (with an inversion on opposite beats) is observed in TS patients with a heart rate of 120 beats/min (an example is shown in Fig. 6E, which was reproduced from Ref.…”

Section: Resultsmentioning

confidence: 68%

L-type Ca²⁺ channel mutations and T-wave alternans: a model study

Zhu¹,

Clancy²

2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Additional cardinal features of TS include: bradycardia, AV-Block, congenital heart disease, immune deficiency, hypoglycemia, neurological and cognitive abnormalities such as intellectual disability, autism and seizures as well as distinctive cranio-facial abnormalities. Also, an association of TS with hypertrophic cardiomyopathy has been described [7]. …”

Section: Introductionmentioning

confidence: 99%

Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2)

et al. 2014

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BackgroundLong-QT syndrome (LQTS) causes a prolongation of the QT-interval in the ECG leading to life threatening tachyarrhythmia and ventricular fibrillation. One atypical form of LQTS, Timothy syndrome (TS), is associated with syndactyly, immune deficiency, cognitive and neurological abnormalities as well as distinct cranio-facial abnormalities.Case presentationOn a family with both children diagnosed with clinical LQTS, we performed whole exome sequencing to comprehensively screen for causative mutations after a targeted candidate gene panel screen for Long-QT syndrome target genes failed to identify any underlying genetic defect. Using exome sequencing, we identified in both affected children, a p.402G > S mutation in exon 8 of the CACNA1C gene, a voltage-dependent Ca2+ channel. The mutation was inherited from their father, a mosaic mutation carrier. Based on this molecular finding and further more careful clinical examination, we refined the diagnosis to be Timothy syndrome (TS2) and thereby were able to present new therapeutic approaches.ConclusionsOur study highlights the difficulties in accurate diagnosis of patients with rare diseases, especially those with atypical clinical manifestation. Such challenge could be addressed with the help of comprehensive and unbiased mutation screening, such as exome sequencing.

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“…Fetal hydrops is considered as obligated consequence of heart failure by sustained episodes of fetal AV dissociation and ventricular arrhythmia [Ishikawa et al, 2013]. A genetic explanation for this prenatal presentation of TS1 is difficult because our propositus and the patient of Lo-A-Njoe et al (2005, patient B) shared the same Ca V 1.2 mutation, as in the others previous patients with proven TS1at the molecular level [Lo-A-Njoe et al, 2005;Splawski et al 2006], but without hydrops. Prenatal drugs could affect the QTc interval of the fetus [Kies et al, 2005], and such exposure could be contributor for fetal hydrops in our patient in relation with the referred use of amitriptyline during the first 4 months of pregnancy, since this tricyclic antidepressant is associated with a significant increase in the QTc interval [van Noord et al, 2009].…”

Section: Discussionmentioning

confidence: 64%

Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1

Corona‐Rivera

Barrios-Prieto

Nieto-García

et al. 2015

European Journal of Medical Genetics

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Syndactyly and long QT syndrome (CaV1.2 missense mutation G406R) is associated with hypertrophic cardiomyopathy

Cited by 30 publications

References 11 publications

L-type Ca²⁺ channel mutations and T-wave alternans: a model study

L-type Ca²⁺ channel mutations and T-wave alternans: a model study

Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2)

Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1

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Syndactyly and long QT syndrome (CaV1.2 missense mutation G406R) is associated with hypertrophic cardiomyopathy

Cited by 30 publications

References 11 publications

L-type Ca2+ channel mutations and T-wave alternans: a model study

L-type Ca2+ channel mutations and T-wave alternans: a model study

Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2)

Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1

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L-type Ca²⁺ channel mutations and T-wave alternans: a model study

L-type Ca²⁺ channel mutations and T-wave alternans: a model study