Other entities represented in this entry:
ORPHA: 101016, 768; DO: 0110650;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p25.3 | Long QT syndrome 9 | 611818 | Autosomal dominant | 3 | CAV3 | 601253 |
A number sign (#) is used with this entry because long QT syndrome-9 (LQT9) is caused by heterozygous mutation in the CAV3 gene (601253), which encodes caveolin-3, on chromosome 3p25.
Digenic inheritance has also been reported; see MOLECULAR GENETICS.
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).
Vatta et al. (2006) identified 6 patients with long QT syndrome and mutation in the CAV3 gene. Patient 1 was a 14-year-old girl who presented with nonexertional syncope with a QTc of 405 ms and U waves and sinus bradycardia on ECG. Her presentation was noted to be 'seizure-like'. This patient was found to carry a mutation in another long QT syndrome gene in addition to mutation in CAV3 (see MOLECULAR GENETICS). Patient 2 was an 8-year-old boy who presented with nonexertional syncope with a QTc of 433 ms and had marked sinus bradycardia. Patient 3 was a 40-year-old man who was asymptomatic with a QTc of 456 ms. Patient 4 was a 36-year-old woman who presented with cardiac arrest in sleep. Patient 5 was a 13-year-old girl with asthma who presented with shortness of breath and chest pain. Her QT prolongation (QTc 532 ms) was present only while on beta-agonist inhaler therapy for her asthma. Patient 6 was a 16-year-old boy who presented with nonexertional syncope and a QTc of 480 ms.
The heterozygous mutations in the CAV3 gene that were identified in patients 4, 5, and 6 with LQT9 by Vatta et al. (2006) occurred de novo. The families of probands 1, 2, and 3 declined genotyping.
Vatta et al. (2006) analyzed the CAV3 gene (601253) in 905 unrelated patients with long QT syndrome who had previously been tested for mutations in known LQT genes; in 6 patients, they identified 4 heterozygous missense mutations (601253.0016-601253.0019, respectively) that were not found in more than 1,000 control alleles. Functional studies showed that the mutant caveolin-3 resulted in a 2- to 3-fold increase in the late sodium current of the cardiac sodium channel compared with wildtype.
Cronk et al. (2007) analyzed the CAV3 gene in necropsy tissue from 134 unrelated cases of sudden infant death syndrome (SIDS; 272120) and identified 3 missense mutations in 3 of 50 black infants (601253.0018; 601253.0020; 601253.0021). No mutations were detected in 1 Hispanic or 83 Caucasian infants. Voltage clamp studies demonstrated a gain-of-function phenotype for all 3 CAV3 mutations, with a 5-fold increase in late sodium current compared to controls.
Digenic Inheritance
Vatta et al. (2006) identified a long QT syndrome patient who had biallelic digenic mutations: a 14-year-old girl with nonexertional syncope and a 'seizure-like' presentation, who had U waves, sinus bradycardia, and a QTc of 405 ms on ECG, was found to carry a missense mutation in the LQT2-associated KCNH2 gene as well as a mutation in the CAV3 gene (see 601253.0018 and 152427.0024).
Cronk, L. B., Ye, B., Kaku, T., Tester, D. J., Vatta, M., Makielski, J. C., Ackerman, M. J. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm 4: 161-166, 2007. [PubMed: 17275750] [Full Text: https://doi.org/10.1016/j.hrthm.2006.11.030]
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]
Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114: 2104-2112, 2006. [PubMed: 17060380] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.106.635268]