Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q43 | Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome | 115000 | Autosomal dominant | 3 | RYR2 | 180902 |
A number sign (#) is used with this entry because of evidence that ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS) is caused by heterozygous mutation in the RYR2 gene (180902) on chromosome 1q43.
Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS) is characterized by syncope, cardiac arrest, and/or sudden unexpected death. Polymorphic ventricular tachycardia and ventricular fibrillation have been documented in these patients. Symptoms generally occur with physical activity or emotional stress, but unlike typical catecholaminergic ventricular tachycardia (CPVT), arrhythmias are not reproducible on exercise stress testing or adrenaline challenge (Sun et al., 2021).
Mutation in the RYR2 gene also causes catecholaminergic polymorphic ventricular tachycardia-1 (CPVT1; 604772).
Sun et al. (2021) reported 17 patients from 6 families with life-threatening ventricular arrhythmias and/or sudden cardiac death (SCD) who had mutations in the RYR2 gene. Patients experienced syncope or cardiac arrest, often in association with physical exertion or acute emotional stress. Polymorphic ventricular tachycardia and/or ventricular fibrillation was documented in patients who survived. All probands showed negative results on exercise stress testing and/or adrenaline challenge, with no ventricular arrhythmias elicited.
The transmission pattern of VACRDS in the families reported by Sun et al. (2021) was consistent with autosomal dominant inheritance.
In 6 families in which the proband experienced SCD or aborted SCD (aSCD), Sun et al. (2021) identified heterozygosity for missense mutations in the RYR2 gene (see, e.g., 180902.0012-180902.0014). Combining these families with 4 previously reported families with RYR2 missense mutations, including a family studied by Priori et al. (2002) (180902.0010), showed that 31 (67%) of 46 mutation carriers experienced SCD or aSCD, whereas none of the 46 mutation-negative individuals had life-threatening ventricular arrhythmias. All of the RYR2 missense mutations showed loss-of-function effects, and Sun et al. (2021) designated the disorder 'RYR2 Ca(2+) release deficiency syndrome (CRDS).' Because the arrhythmias in these patients are not reproducible on exercise stress testing or adrenaline challenge, the authors developed a ventricular pacing protocol to unmask the condition before potentially lethal events manifest, and were successful in eliciting polymorphic ventricular arrhythmias in 2 patients using the 3-component stimulation sequence.
Kuhn et al. (1964) described 2 sisters with polymorphic and polytopic ventricular extrasystoles. One had syncopal attacks. A brother died suddenly at age 10 and the mother at age 40, under circumstances suggesting the presence of the same disorder.
Berg, K. J. Multifocal ventricular extrasystoles with Adams-Stokes syndrome in siblings. Am. Heart J. 60: 965-970, 1960.
Gault, J. H., Cantwell, J., Lev, M., Braunwald, E. Fatal familial cardiac arrhythmias. Am. J. Cardiol. 29: 548-553, 1972. [PubMed: 5016833] [Full Text: https://doi.org/10.1016/0002-9149(72)90447-x]
Kuhn, E., Wolf, D., Stieler, M. Familial polytopic and polymorphic extrasystoles. Jpn. Heart J. 5: 81-84, 1964. [PubMed: 14115011] [Full Text: https://doi.org/10.1536/ihj.5.81]
Priori, S. G., Napolitano, C., Memmi, M., Colombi, B., Drago, F., Gasparini, M., DeSimone, L., Coltorti, F., Bloise, R., Keegan, R., Cruz Filho, F. E. S., Vignati, G., Benatar, A., DeLogu, A. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 106: 69-74, 2002. [PubMed: 12093772] [Full Text: https://doi.org/10.1161/01.cir.0000020013.73106.d8]
Sacks, H. S., Matisonn, R., Kennelly, B. M. Familial paroxysmal ventricular tachycardia in two sisters. Am. Heart J. 87: 217-222, 1974. [PubMed: 4129426] [Full Text: https://doi.org/10.1016/0002-8703(74)90044-1]
Sun, B., Yao, J., Ni, M., Wei, J., Zhong, X., Guo, W., Zhang, L., Wang, R., Belke, D., Chen, Y.-X., Lieve, K. V. V., Broendberg, A. K., and 19 others. Cardiac ryanodine receptor calcium release deficiency syndrome. Sci. Transl. Med. 13: eaba7287, 2021. [PubMed: 33536282] [Full Text: https://doi.org/10.1126/scitranslmed.aba7287]
Waynberger, M., Courtadon, M., Peltier, J.-M., Ducloux, G., Jallut, H., Slama, R. Tachycardies ventriculaires familiales: a propos de 7 observations. Presse Med. 14: 1857-1860, 1974.