Penetrance and expressivity of the R858H <i>CACNA1C</i> variant in a five‐generation pedigree segregating an arrhythmogenic channelopathy

Gardner, R. J McKinlay; Crozier, Ian; Binfield, Alex; Love, Donald R.; Lehnert, Klaus; Gibson, Kate; Lintott, Caroline J.; Snell, Russell G.; Jacobsen, Jessie C.; Jones, Peter P.; Waddell-Smith, K.; Kennedy, Martin A.; Skinner, Jonathan R.

doi:10.1002/mgg3.476

Cited by 11 publications

(4 citation statements)

References 47 publications

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“…This variant is positioned on the cytoplasmic loop between S4 and S5 of domain II in the CACNA1C channel. Variants associated with LQT8 have also been identified on cytoplasmic loops in domain II, in the loop between domain II and III, and on the C-terminal cytoplasmic tail of this channel (11,36,37). This is the first case report of a similarly-located variant that resulted in a TS diagnosis.…”

Section: Atypical Timothy Syndromementioning

confidence: 74%

Update on the Molecular Genetics of Timothy Syndrome

Bauer

Timothy²,

Golden

2021

Front. Pediatr.

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Timothy Syndrome (TS) (OMIM #601005) is a rare autosomal dominant syndrome caused by variants in CACNA1C, which encodes the α1C subunit of the voltage-gated calcium channel Cav1.2. TS is classically caused by only a few different genetic changes and characterized by prolonged QT interval, syndactyly, and neurodevelopmental delay; however, the number of identified TS-causing variants is growing, and the resulting symptom profiles are incredibly complex and variable. Here, we aim to review the genetic and clinical findings of all published case reports of TS to date. We discuss multiple possible mechanisms for the variability seen in clinical features across these cases, including mosaicism, genetic background, isoform complexity of CACNA1C and differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. Finally, we propose future research directions such as variant validation, in vivo modeling, and natural history characterization.

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Section: Atypical Timothy Syndromementioning

confidence: 74%

Update on the Molecular Genetics of Timothy Syndrome

Bauer

Timothy²,

Golden

2021

Front. Pediatr.

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“…We found two variants in CACNA1C , one of which was located in the intracellular loop linking repeat III and IV (c.3575A>T; p.Q1192L). Several variants located in the cytosolic loop have been reported as LQTS-related ones, suggesting that gain-of-function mutations affect the function of CACNA1C [ 5 , 55 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted deep sequencing analyses of long QT syndrome in a Japanese population

et al. 2022

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Long QT syndrome (LQTS) is one of the most common inherited arrhythmias and multiple genes have been reported as causative. Presently, genetic diagnosis for LQTS patients is becoming widespread and contributing to implementation of therapies. However, causative genetic mutations cannot be detected in about 20% of patients. To elucidate additional genetic mutations in LQTS, we performed deep-sequencing of previously reported 15 causative and 85 candidate genes for this disorder in 556 Japanese LQTS patients. We performed in-silico filtering of the sequencing data and found 48 novel variants in 33 genes of 53 cases. These variants were predicted to be damaging to coding proteins or to alter the binding affinity of several transcription factors. Notably, we found that most of the LQTS-related variants in the RYR2 gene were in the large cytoplasmic domain of the N-terminus side. They might be useful for screening of LQTS patients who had no known genetic factors. In addition, when the mechanisms of these variants in the development of LQTS are revealed, it will be useful for early diagnosis, risk stratification, and selection of treatment.

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“…The variant p.P857L has previously been reported in three unrelated individuals amongst a cohort of 174 cardiac arrest survivors without a clear phenotype undergoing genetic testing 24 . In addition, a recent report of a large family with the p.R858H variant demonstrated similar discordance between arrhythmic events and QT prolongation 25 . The authors even conclude the term 'arrhythmogenic channelopathy' may be more appropriate than LQTS in this family.…”

Section: Phenotypementioning

confidence: 67%

Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site

et al. 2019

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Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

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Penetrance and expressivity of the R858H CACNA1C variant in a five‐generation pedigree segregating an arrhythmogenic channelopathy

Cited by 11 publications

References 47 publications

Update on the Molecular Genetics of Timothy Syndrome

Update on the Molecular Genetics of Timothy Syndrome

Targeted deep sequencing analyses of long QT syndrome in a Japanese population

Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site

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