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Other entities represented in this entry:
SNOMEDCT: 74390002; ICD10CM: I45.6; DO: 384;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q36.1 | Wolff-Parkinson-White syndrome | 194200 | Autosomal dominant | 3 | PRKAG2 | 602743 |
A number sign (#) is used with this entry because of evidence that Wolff-Parkinson-White syndrome (WPW) is caused by heterozygous mutation in the gamma-2 regulatory subunit of AMP-activated protein kinase (PRKAG2; 602743) on chromosome 7q36.
Mutation in the PRKAG2 gene can also cause a form of hypertrophic cardiomyopathy in which some patients exhibit WPW (CMH6; 600858).
The features of this electrocardiographic syndrome are short PR interval and prolonged QRS, specifically with a slurred-up stroke of the R wave called a delta wave. The patients are prone to paroxysmal supraventricular tachycardia. The familial occurrence of the Wolff-Parkinson-White syndrome has been reported many times (Harnischfeger, 1959). In at least 2 reported families it has been associated with familial cardiomyopathy (Massumi, 1967). Schneider (1969) observed an affected mother and son. Chia et al. (1982) described a Chinese family in which the WPW syndrome was present in a 21-year-old male (who came to medical attention because of palpitations occasioned by paroxysmal atrial fibrillation) and in his father and 2 of his 5 brothers. One of the brothers died suddenly at age 19 years. Autopsy showed no gross cardiac abnormality but detailed examination of the conduction system was not done. A sister, aged 16 years, showed Lown-Ganong-Levine (LGL) preexcitation.
Vidaillet et al. (1987) determined the prevalence of preexcitation in the first-degree relatives of 383 patients with electrophysiologically proved accessory atrioventricular pathways. In 13 of the 383 patients (3.4%), accessory pathways were documented in 1 or more first-degree relatives. Patients with familial preexcitation had a higher incidence of multiple accessory pathways and possibly an increased risk of sudden cardiac death. Vidaillet et al. (1987) suggested that an autosomal dominant factor is involved. The early study of Warner and McKusick (1958) was cited.
Gollob et al. (2001) evaluated 2 families segregating autosomal dominant WPW syndrome in which the probands presented with syncope and characteristic electrocardiographic features. The clinical symptoms typically had their onset in late adolescence or the third decade of life. In addition to preexcitation, other forms of conduction disease were seen, including progression to high-grade sinoatrial or atrioventricular block requiring pacemaker implantation in 76% of affected members of both families older than 30 years of age. Cardiac hypertrophy was identified in 8 (26%) of 31 affected individuals who were evaluated.
Anderson et al. (2001) emphasized the importance of careful definition of the phenotype in studies of presumed familial WPW syndrome. They quoted Vidaillet et al. (1987) as suggesting that in familial WPW syndrome structural changes are rare. On the other hand, Gollob et al. (2001) pointed to the report by Mehdirad et al. (1999) of typical accessory atrioventricular bundles in members of a family with a clinical syndrome identical to the one described by Gollob et al. (2001).
Five to 10% of hypertrophic cardiomyopathy (see 192600) patients have ventricular preexcitation. An association between WPW and familial hypertrophic cardiomyopathy had been noted in earliest descriptions of the latter condition. Braunwald et al. (1960) proposed that abnormal ventricular activation might result in regional myocardial hypertrophy or that localized hypertrophy might disrupt normal cardiac electrical discontinuity at the atrial ventricular ring.
Kimura et al. (1997) presented data indicating that the WPW syndrome can be associated with more than one type of CMH. They observed WPW in 3 individuals with the gly203-to-ser mutation in the cardiac troponin I gene (191044) and in 1 individual with a 2-bp deletion at codon 945 in the cardiac myosin-binding protein C gene (600958), which is the site of the mutation in familial hypertrophic cardiomyopathy 4 (CMH4; 115197). Kimura et al. (1997) noted that they had also found the 2-bp MYBPC3 deletion in 3 other CMH patients without WPW.
Ventricular fibrillation can be the presenting arrhythmia in children with asymptomatic WPW syndrome. Pappone et al. (2004) concluded that deaths due to this arrhythmia are potentially preventable. In asymptomatic, high-risk children, prophylactic catheter ablation performed by an experienced operator reduced the risk of life-threatening arrhythmias. In 47 asymptomatic children with WPW syndrome ablation was performed in 20 and no ablation in 27. The characteristics of the 2 groups as to the presence of multiple accessory pathways (which has a worse prognosis) was essentially identical. At 40 months of follow-up, 19 of the 20 ablation patients were alive and free of arrhythmic events; 44% of the high risk patients who did not undergo prophylactic ablation had arrhythmic events, including cardiac arrest or sudden death, during the first 2 years of follow-up.
WPW syndrome is the second most common cause of paroxysmal supraventricular tachycardia in most parts of the world and is the most common cause in China, being responsible for more than 70% of cases (Wan et al., 1992).
In a large family with 25 surviving individuals affected by WPW syndrome, familial hypertrophic cardiomyopathy or both, MacRae et al. (1995) found close linkage to DNA markers on 7q3.
By haplotype analysis in 2 families segregating WPW in an autosomal dominant inheritance pattern, Gollob et al. (2001) demonstrated mapping of the disorder to 7q34-q36, the same region identified by MacRae et al. (1995).
The transmission pattern of WPW in the families reported by Gollob et al. (2001) was consistent with autosomal dominant inheritance.
Gollob et al. (2001) noted that the PRKAG2 gene is located in the critical genomic region of the WPW syndrome locus identified by linkage on chromosome 7q34-q36. In affected members of 2 families with WPW syndrome, they identified an arg302-to-gln mutation (R302N; 602743.0001) in the PRKAG2 gene. An additional sequence variation at nucleotide 1912 in the 3-prime untranslated region of PRKAG2 was present in all affected members of family 2 but not family 1, indicating that the 2 families were unrelated.
Gollob et al. (2001) reported a third, unrelated family in which affected members manifested ventricular preexcitation, atrial fibrillation, and conduction defects from childhood. Cardiac hypertrophy was absent. The molecular defect in this family was an arg531-to-gly mutation (R531G; 602743.0006) in the PRKAG2 gene.
Anderson, K. P., Vidaillet, H. J., Jr., Josephson, M. E. A gene responsible for familial Wolff-Parkinson-White syndrome. (Letter) New Eng. J. Med. 345: 1063 only, 2001. [PubMed: 11586962] [Full Text: https://doi.org/10.1056/NEJM200110043451412]
Braunwald, E., Morrow, A. G., Cornell, W. P., Aygen, M. M., Hilbish, T. F. Idiopathic hypertrophic subaortic stenosis: clinical, hemodynamic and angiographic manifestations. Am. J. Med. 29: 924-945, 1960.
Chia, B. L., Yew, F. C., Chay, S. O., Tan, A. T. H. Familial Wolff-Parkinson-White syndrome. J. Electrocardiol. 15: 195-198, 1982. [PubMed: 7069337] [Full Text: https://doi.org/10.1016/s0022-0736(82)80016-2]
Gillette, P. C., Freed, D., McNamara, D. G. A proposed autosomal dominant method of inheritance of the Wolff-Parkinson-White syndrome and supraventricular tachycardia. J. Pediat. 93: 257-258, 1978. [PubMed: 671163] [Full Text: https://doi.org/10.1016/s0022-3476(78)80511-3]
Gollob, M. H., Green, M. S., Roberts, R. A gene responsible for familial Wolff-Parkinson-White syndrome. (Letter) New Eng. J. Med. 345: 1063-1064, 2001.
Gollob, M. H., Green, M. S., Tang, A. S.-L., Gollob, T., Karibe, A., Al Sayegh, A. H., Ahmad, F., Lozado, R., Shah, G., Fananapazir, L., Bachinski, L. L., Roberts, R. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. New Eng. J. Med. 344: 1823-1831, 2001. Note: Erratum. New Eng. J. Med. 345: 552 only, 2001; Erratum: New Eng. J. Med. 346: 300 only, 2002. [PubMed: 11407343] [Full Text: https://doi.org/10.1056/NEJM200106143442403]
Gollob, M. H., Seger, J. J., Gollob, T. N., Tapscott, T., Gonzales, O., Bachinski, L., Roberts, R. Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy. Circulation 104: 3030-3033, 2001. [PubMed: 11748095] [Full Text: https://doi.org/10.1161/hc5001.102111]
Harnischfeger, W. W. Hereditary occurrence of the pre-excitation (Wolff-Parkinson-White) syndrome with re-entry mechanism and concealed conduction. Circulation 19: 28-40, 1959. [PubMed: 13619017] [Full Text: https://doi.org/10.1161/01.cir.19.1.28]
Kimura, A., Harada, H., Park, J.-E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.-H., Choo, J., Chung, K.-S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nature Genet. 16: 379-382, 1997. [PubMed: 9241277] [Full Text: https://doi.org/10.1038/ng0897-379]
MacRae, C. A., Ghaisas, N., Kass, S., Donnelly, S., Basson, C. T., Watkins, H. C., Anan, R., Thierfelder, L. H., McGarry, K., Rowland, E., McKenna, W. J., Seidman, J. G., Seidman, C. E. Familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3. J. Clin. Invest. 96: 1216-1220, 1995. [PubMed: 7657794] [Full Text: https://doi.org/10.1172/JCI118154]
Massumi, R. A. Familial Wolff-Parkinson-White syndrome with cardiomyopathy. Am. J. Med. 43: 951-955, 1967. [PubMed: 4228766] [Full Text: https://doi.org/10.1016/0002-9343(67)90254-9]
Mehdirad, A. A., Fatkin, D., DiMarco, J. P., et al. Electrophysiologic characteristics of accessory atrioventricular connections in an inherited form of Wolff-Parkinson-White syndrome. J. Cardiovasc. Electrophysiol. 10: 629-635, 1999. [PubMed: 10355918] [Full Text: https://doi.org/10.1111/j.1540-8167.1999.tb00239.x]
Morooka, S., Kato, A., Murao, S., Ohsuzu, H. A 17-year follow-up of a family with idiopathic hypertrophic cardiomyopathy and WPW syndrome. Jpn. Heart J. 19: 332-345, 1978. [PubMed: 567705] [Full Text: https://doi.org/10.1536/ihj.19.332]
Pappone, C., Manguso, F., Santinelli, R., Vicedomini, G., Sala, S., Paglino, G., Mazzone, P., Lang, C. C., Gulletta, S., Augello, G., Santinelli, O., Santinelli, V. Radiofrequency ablation in children with asymptomatic Wolff-Parkinson-White syndrome. New Eng. J. Med. 351: 1197-1205, 2004. [PubMed: 15371577] [Full Text: https://doi.org/10.1056/NEJMoa040625]
Schneider, R. G. Familial occurrence of Wolff-Parkinson-White syndrome. Am. Heart J. 78: 34-36, 1969. [PubMed: 5794793] [Full Text: https://doi.org/10.1016/0002-8703(69)90255-5]
Vidaillet, H. J., Jr., Pressley, J. C., Henke, E., Harrell, F. E., Jr., German, L. D. Familial occurrence of accessory atrioventricular pathways (preexcitation syndrome). New Eng. J. Med. 317: 65-69, 1987. [PubMed: 3587328] [Full Text: https://doi.org/10.1056/NEJM198707093170201]
Wan, Q., Wu, N., Fan, W., Tang, Y., Jin, L., Fang, Q. Clinical manifestations and prevalence of different types of supraventricular tachycardia among Chinese. Chin. Med. J. 105: 284-288, 1992. [PubMed: 1618009]
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