SNOMEDCT: 1230096008; ORPHA: 65283, 768; DO: 0110649;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.33 | Long QT syndrome 8 | 618447 | Autosomal dominant | 3 | CACNA1C | 114205 |
A number sign (#) is used with this entry because of evidence that long QT syndrome-8 (LQT8) is caused by heterozygous mutation in the CACNA1C gene (114205) on chromosome 12p13.
Mutation in the CACNA1C gene can also cause Brugada syndrome (BRGDA3; 611875) and Timothy syndrome (TS; 601005).
Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (Jongbloed et al., 1999).
For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (192500).
Boczek et al. (2013) reported 2 families with long QT syndrome and mutation in the CACNA1C gene. In the first family, the proband was a 33-year-old woman who presented at age 27 with a postpartum agonal breathing event. History revealed multiple startle-triggered and exercise-induced syncopal events starting at age 13 years. Her ECG revealed a prolonged QTc of 498 ms. A cardioverter-defibrillator was implanted. One of the proband's maternal aunts had a cardiac arrest at age 44 years, which resulted in significant neurologic damage. A second maternal aunt died during infancy of unknown cause. A third maternal aunt had a syncopal event during pregnancy (QTc = 479 ms). The proband's daughter was being treated with prophylactic beta-block therapy since the age of 8 years (QTc = 450 ms). The proband's asymptomatic mother had a prolonged QTc of 486 ms. The ECG of the proband's asymptomatic maternal uncle showed sinus bradycardia, early repolarization, and a QTc of 454 ms. In the second family, the proband was a 15-year-old boy who was diagnosed with LQT8 (Qtc of 514 ms) after the sudden unexplained death of his 12-year-old sister during sleep. His mother, maternal grandmother, maternal great uncle, and maternal great aunt all had a history of syncopal events during childhood.
Fukuyama et al. (2014) reported 7 patients from 5 Japanese families with LQT8. Prolonged QTc ranged from 420 ms to 597 ms in the probands.
Gardner et al. (2019) reported affected members of a 5-generation European family with LQT8. The phenotype in the family was highly variable and ranged from no apparent effect, through asymptomatic QT interval prolongation on ECG, to episodes of presyncope and syncope, ventricular fibrillation, and sudden death. QT prolongation showed inconsistent correlation with functional cardiology.
The transmission pattern of LQT8 in the family reported by Boczek et al. (2013) was consistent with autosomal dominant inheritance.
In the 5-generation family reported by Gardner et al. (2019), the transmission pattern of LQT8 was consistent with autosomal dominant inheritance with incomplete penetrance.
By trio-based whole-exome sequencing in a large multigeneration family segregating long QT syndrome without mutation in known causative genes, Boczek et al. (2013) identified heterozygosity for a missense mutation in the CACNA1C gene (P857R; 114205.0005) that segregated with the disorder in the family. By sequencing the CACNA1C gene in 102 unrelated patients with LQTS without a molecular basis, Boczek et al. (2013) identified 3 patients with heterozygous mutations in the CACNA1C gene (see, e.g., P857L, 114205.0006 and K834E, 114205.0007).
By screening 278 Japanese probands with LQT who were negative for mutation in known causative genes, Fukuyama et al. (2014) identified 5 novel CACNA1C variants (see, e.g., R858H, 114205.0008 and A582D, 114205.0009) in 7 probands. The variants were absent in the NHLBI Exome Variant Server database and in 500 reference alleles from 250 Japanese controls.
By Sanger sequencing of the genes causing LQT1 through LQT8 in 540 probands with LQT, Wemhoner et al. (2015) identified 6 patients with heterozygous mutations in the CACNA1C gene (see, e.g., I1475M, 114205.0010).
In affected members of a 5-generation European family with LQT8, Gardner et al. (2019) identified heterozygosity for the R858H mutation in the CACNA1C gene that was previously identified by Fukuyama et al. (2014) in Japanese patients.
Boczek, N. J., Best, J. M., Tester, D. J., Giudicessi, J. R., Middha, S., Evans, J. M., Kamp, T. J., Ackerman, M. J. Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ. Cardiovasc. Genet. 6: 279-289, 2013. [PubMed: 23677916] [Full Text: https://doi.org/10.1161/CIRCGENETICS.113.000138]
Fukuyama, M., Wang, Q., Kato, K., Ohno, S., Ding, W.-G., Toyoda, F., Itoh, H., Kimura, H., Makiyama, T., Ito, M., Matsuura, H., Horie, M. Long QT syndrome type 8: novel CACNA2C mutations causing QT prolongation and variant phenotypes. Europace 16: 1828-1837, 2014. [PubMed: 24728418] [Full Text: https://doi.org/10.1093/europace/euu063]
Gardner, R. J. M., Crozier, I. G., Binfield, A. L., Love, D. R., Lehnert, K., Gibson, K., Lintott, C. J., Snell, R. G., Jacobsen, J. C., Jones, P. P., Waddell-Smith, K. E., Kennedy, M. A., Skinner, J. R. Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy. Molec. Genet. Genomic Med. 7: e00476, 2019. Note: Electronic Article. [PubMed: 30345660] [Full Text: https://doi.org/10.1002/mgg3.476]
Jongbloed, R. J. E., Wilde, A. A. M., Geelen, J. L. M. C., Doevendans, P., Schaap, C., Van Langen, I., van Tintelen, J. P., Cobben, J. M., Beaufort-Krol, G. C. M., Geraedts, J. P. M., Smeets, H. J. M. Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. Hum. Mutat. 13: 301-310, 1999. [PubMed: 10220144] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V]
Wemhoner, K., Friedrich, C., Stallmeyer, B., Coffey, A. J., Grace, A., Zumhagen, S., Seebohm, G., Ortiz-Bonnin, B., Rinne, S., Sachse, F. B., Shulze-Bahr, E., Decher, N. Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome. J. Molec. Cell. Cardiol. 80: 186-195, 2015. [PubMed: 25633834] [Full Text: https://doi.org/10.1016/j.yjmcc.2015.01.002]