Alternative titles; symbols
SNOMEDCT: 268185002; ICD10CM: Q25.3; ORPHA: 3193; DO: 1929;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q11.23 | Supravalvar aortic stenosis | 185500 | Autosomal dominant | 3 | ELN | 130160 |
A number sign (#) is used with this entry because supravalvular aortic stenosis (SVAS) is caused by heterozygous mutation in the gene encoding elastin (ELN; 130160) on chromosome 7q11.
SVAS is a frequent feature of Williams-Beuren syndrome (WBS; 194050), a contiguous gene deletion syndrome that includes hemizygous deletion of the ELN gene.
Eisenberg et al. (1964) reported 22 cases of supravalvular aortic stenosis involving 3 generations of each of 2 families. Some had associated pulmonary valvular or peripheral arterial stenosis. None had unusual facies.
Gyllensward et al. (1957) reported pulmonary artery stenosis in mother and son.
Lewis et al. (1969) described a sibship in which 5 of 9 sibs had supravalvar aortic stenosis with peculiar facies but normal intelligence. Schmidt et al. (1989) reevaluated this family and provided examinations of the parents, additional sibs, and offspring of the original 5 patients. Echocardiographic examinations added to the completeness of the survey. The SVAS showed marked variability of expression and was not associated with mental retardation. It also was said not to be associated with the facial manifestations of Williams syndrome, but the photographs seem to belie that conclusion: the configuration of the mouth in patients III-16 and III-18 who had SVAS documented by echocardiogram is very suggestive of the Williams syndrome and is quite different from that in their brother, III-17, who had a normal echocardiogram. Schmidt et al. (1989) concluded that isolated SVAS and Williams syndrome represent 'clinically distinct entities.' They did not commit themselves as to whether there was any genetic relationship between the two.
Antia et al. (1967) commented on a lack of clear distinction between the familial supravalvular aortic stenosis with normal facies and mentality and the nonfamilial type with abnormal facies and mental retardation.
McDonald et al. (1969) described an arteriopathy, with multiple pulmonary and systemic arterial stenoses, in a mother and 3 daughters. Two had supravalvular aortic stenosis. The familial occurrence of pulmonary arterial stenoses is documented (McCue et al., 1965) and their occurrence after maternal rubella is well established (Rowe, 1963). It can be argued that supravalvular aortic stenosis is an inadequate or inappropriate designation.
Strong et al. (1970) observed sudden death following premedication for cardiac catheterization in an 11-month-old male. Postmortem showed severe fibromuscular dysplasia of both systemic and pulmonary arteries. A sister had signs of mild pulmonary artery and supravalvular aortic stenosis. The mother had signs of mild aortic stenosis.
Wooley et al. (1961) described sibs with supravalvular aortic stenosis.
McKusick (1978) saw a family in which a man, his son and daughter, and his paternal uncle had well-confirmed signs of supravalvular aortic stenosis and/or peripheral pulmonary stenoses. None had manifestations of Williams syndrome.
O'Connor et al. (1985) studied 6 patients with supravalvular aortic stenosis; 3 had Williams syndrome, 2 had familial SVAS (presumably without evidence of Williams syndrome), and 1 had sporadic SVAS.
The existence of a familial form of SVAS, which might be called the Eisenberg form, separate from the SVAS in the Williams-Beuren syndrome appeared to be established by a study of an extensive kindred with 36 affected persons in 5 generations (Chiarella et al., 1989). The unique study was made possible by the fact that the family had lived in relative isolation on a small island in the Sardinian archipelago for over 200 years and also by the availability of echocardiography, including portable equipment usable in the home, for noninvasive diagnosis. Penetrance was estimated to be 86%. In 5 of 8 patients who underwent cardiac catheterization, multiple pulmonary stenoses were observed. Surgical correction was performed in 4 cases. None of the affected family members had unusual facies or mental retardation.
A similar family with the Eisenberg form of SVAS was reported by Ensing et al. (1989). Three members of that family had supravalvular aortic stenosis requiring surgery. Of 22 members examined echocardiographically who had not had prior surgical repair, 13 had supravalvular aortic stenosis. The echocardiographic findings varied widely, from calcification of the ascending aorta in a 71-year-old man with minimally increased flow velocity, to mild narrowing with mildly increased flow velocity in 6 members, to significant narrowing with impressively increased flow velocity in 7. In addition, 4 patients had mild narrowing of pulmonary artery branches and 8 had peak pulmonary artery flow velocities above normal. The family was of Irish-Native American-English descent living in the United States.
Kumar et al. (1993) observed 5 affected persons in 1 family; 3 had isolated SVAS, 1 had isolated peripheral pulmonary stenosis (PPS), and 1 had SVAS and PPS.
In a family with autosomal dominant SVAS, Curran et al. (1993) found that a translocation t(6;7)(p21.1;q11.23) that cosegregated with the disease also disrupted the elastin gene (130160). The breakpoint was localized to exon 28 of the gene. Combined with studies indicating linkage of SVAS to the elastin gene (Ewart et al., 1993), the data suggested that mutations in the elastin gene are the cause of SVAS. Ewart et al. (1993) found a combined lod score of 5.90 for linkage of SVAS with the ELN gene, which has been mapped to 7q11.2. In a large 3-generation family, Olson et al. (1993) found linkage to a highly informative (CA)n repeat marker at locus D7S440 which had been localized to 7q. The findings are entirely consistent with the evidence implicating the elastin gene in the causation of this abnormality.
Kumar et al. (1994) confirmed the linkage of supravalvular aortic stenosis to the elastin gene. In the family they studied, individuals in 4 sibships in 3 generations and, by inference, a patient in an earlier generation were affected. Three individuals had supravalvular aortic stenosis; one had peripheral pulmonary stenosis; and one had both.
Exclusion Studies
Bennett et al. (1988) excluded the calcitonin gene (114130) as the site of the mutation in SVAS by use of a gene-specific probe which failed to show concordant segregation. In a family with many affected members with SVAS previously reported by Schmidt et al. (1989), Pastores et al. (1992) also excluded the calcitonin gene as the site of the mutation. Linkage was ruled out.
Morris et al. (1993) reported on the family in which SVAS cosegregated with a familial 6;7 translocation that disrupted the elastin gene at exon 28 (Curran et al., 1993). They pointed out that main pulmonary artery hypoplasia, preductal coarctation of the aorta, and pulmonic stenosis are frequently noted in patients with deletions involving the 7q11 region. Some of the patients have facial features such as wide mouth, long and prominent philtrum, and full lips like those in Williams syndrome.
Von Dadelszen et al. (2000) reported a patient with a de novo translocation 46,XX,t(6;7)(q27;q11.23). Since the Williams syndrome critical region probe showed 3 signals on FISH analysis (1 on the normal chromosome 7, 1 on the derivative 7 at 7q11.23, and a smaller signal on the derivative 6 chromosome at the translocation breakpoint), it appeared that the translocation may have disrupted the elastin gene. The patient presented prenatally with hydrops fetalis and severe supravalvular aortic and pulmonary stenosis, and died shortly after delivery at 32 weeks' gestation. Given the degree of body edema and prematurity, the authors were unable to distinguish between isolated SVAS and Williams syndrome in this patient.
In a family with SVAS, Ewart et al. (1994) found a heterozygous 100-kb deletion in the 3-prime end of the elastin gene with a breakpoint between elastin exons 27 and 28. The same region was disrupted in the familial reciprocal translocation reported by Morris et al. (1993). Ewart et al. (1993) found that deletion involving 7q11.23 and resulting in hemizygosity of the elastin gene is responsible for the Williams-Beuren syndrome (194050). Deletions limited to the elastin gene appear to result in SVAS, whereas deletions spanning at least 114 kb lead to Williams-Beuren syndrome.
Olson et al. (1995) used Southern blot analysis to screen for mutations in the ELN gene in 6 familial and 3 sporadic cases of SVAS. The familial cases included members of the large Middle Eastern pedigree in which linkage to the elastin gene region had been found by Olson et al. (1993). A 30-kb deletion extending from breakpoints in intron 1 and intron 27 (130160.0002) was identified in 2 members of the Middle Eastern family. The proband developed severe SVAS and peripheral pulmonary artery stenosis and underwent aortic operation in early childhood. He had no evidence of Williams syndrome or clinically apparent abnormalities of other elastin-containing tissue. The deletion was also demonstrated in his mother, an obligate carrier with subtle disease (a heart murmur and a nondiagnostic echocardiogram). Blood for DNA analysis was not available from a maternal uncle with SVAS and a sister with isolated peripheral pulmonary artery stenosis.
Li et al. (1997) identified a heterozygous nonsense mutation in the ELN gene (130160.0003) in a sporadic case of SVAS.
Metcalfe et al. (2000) described the mutation spectrum of the ELN gene in 35 unrelated patients with SVAS and normal karyotypes without major deletions of the ELN gene as determined by FISH. A marked phenotypic intrafamilial variability was illustrated by 2 large families with multiple affected members with disease severity ranging from asymptomatic carriers to mild or severe SVAS requiring surgery, or sudden infant death. No obvious genotype-phenotype correlation was detected; cases with missense or splicing mutations were as likely to have severe SVAS as cases with truncating mutations.
Tassabehji et al. (1997) found that isolated SVAS was associated with point mutations in the ELN gene that predicted premature chain termination. They stated that in their experience all patients with a classic Williams syndrome phenotype (194050) had been found to be hemizygous at the elastin locus; nevertheless, only 5% had severe clinical SVAS. In their 2 SVAS families with point mutations, each mutation manifested as severe SVAS in the proband, but as mild cardiac features or nonpenetrance in the mothers. Tassabehji et al. (1997) considered such variability typical of phenotypes produced by haploinsufficiency, where genetic background is expected to have a major modifying effect. An alternative hypothesis is that a dominant-negative elastin mutation results if truncated proteins have some but not all domains critical for intermolecular interactions and thus may disrupt posttranslational processing and development of elastic fibers.
Micale et al. (2010) analyzed the ELN gene in 31 familial and sporadic cases of SVAS and identified 7 novel mutations, including 5 frameshift mutations and 2 splice site mutations (see, e.g., 130160.0020). In vitro analysis of 3 of the frameshift mutations using minigene constructs and transfection assays confirmed that functional haploinsufficiency of the ELN gene is the main pathomechanism underlying SVAS. In addition, molecular analysis of patient fibroblasts showed that the 2044+5G-C (130160.0020) mutant allele encodes an aberrant shorter form of the elastin polypeptide that may hamper the normal assembly of elastin fibers in a dominant-negative manner.
Antia, A. U., Wiltse, H. E., Rowe, R. D., Pitt, E. L., Levin, S., Ottesen, O. E., Cooke, R. E. Pathogenesis of the supravalvular aortic stenosis syndrome. J. Pediat. 71: 431-441, 1967. [PubMed: 6039813] [Full Text: https://doi.org/10.1016/s0022-3476(67)80308-1]
Bennett, C. P., Burn, J., Moore, G. E., Chambers, J., Williamson, R., Wilkinson, J. Exclusion of calcitonin as a candidate gene for the basic defect in a family with autosomal dominant supravalvular aortic stenosis. J. Med. Genet. 25: 311-312, 1988. [PubMed: 3164411] [Full Text: https://doi.org/10.1136/jmg.25.5.311]
Chiarella, F., Dagna Bricarelli, F., Lupi, G., Bellotti, P., Domenicucci, S., Vecchio, C. Familial supravalvular aortic stenosis: a genetic study. J. Med. Genet. 26: 86-92, 1989. [PubMed: 2918546] [Full Text: https://doi.org/10.1136/jmg.26.2.86]
Curran, M. E., Atkinson, D. L., Ewart, A. K., Morris, C. A., Leppert, M. F., Keating, M. T. The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis. Cell 73: 159-168, 1993. [PubMed: 8096434] [Full Text: https://doi.org/10.1016/0092-8674(93)90168-p]
Eisenberg, R., Young, D., Jacobson, B., Boito, A. Familial supravalvar aortic stenosis. Am. J. Dis. Child. 108: 341-347, 1964. [PubMed: 14186652] [Full Text: https://doi.org/10.1001/archpedi.1964.02090010343002]
Ensing, G. J., Schmidt, M. A., Hagler, D. J., Michels, V. V., Carter, G. A., Feldt, R. H. Spectrum of findings in a family with nonsyndromic autosomal dominant supravalvular aortic stenosis: a Doppler echocardiographic study. J. Am. Coll. Cardiol. 13: 413-419, 1989. [PubMed: 2913119] [Full Text: https://doi.org/10.1016/0735-1097(89)90520-2]
Ewart, A. K., Jin, W., Atkinson, D., Morris, C. A., Keating, M. T. Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene. J. Clin. Invest. 93: 1071-1077, 1994. [PubMed: 8132745] [Full Text: https://doi.org/10.1172/JCI117057]
Ewart, A. K., Morris, C. A., Ensing, G. J., Loker, J., Moore, C., Leppert, M., Keating, M. A human vascular disorder, supravalvular aortic stenosis, maps to chromosome 7. Proc. Nat. Acad. Sci. 90: 3226-3230, 1993. [PubMed: 8475063] [Full Text: https://doi.org/10.1073/pnas.90.8.3226]
Gyllensward, A., Lodin, H., Lundberg, A., Moller, T. Congenital, multiple peripheral stenosis of the pulmonary artery. Pediatrics 19: 399-410, 1957. [PubMed: 13408018]
Johnson, L. W., Fishman, R. A., Schneider, B., Parker, F. B., Jr., Husson, G. S., Webb, W. R. Familial supravalvular aortic stenosis: report of a large family and review of the literature. Chest 70: 494-500, 1976. [PubMed: 975952] [Full Text: https://doi.org/10.1378/chest.70.4.494]
Jorgensen, G., Beuren, A. J. Genetische Untersuchungen bei supravalvularen Aortenstenosen. Humangenetik 1: 497-515, 1965. [PubMed: 5868428] [Full Text: https://doi.org/10.1007/BF00338340]
Kumar, A., Olson, T. M., Thibodeau, S. N., Michels, V. V., Schaid, D. J., Wallace, M. R. Confirmation of linkage of supravalvular aortic stenosis to the elastin gene on chromosome 7q. Am. J. Cardiol. 74: 1281-1283, 1994. [PubMed: 7977109] [Full Text: https://doi.org/10.1016/0002-9149(94)90567-3]
Kumar, A., Stalker, H. J., Williams, C. A. Concurrence of supravalvular aortic stenosis and peripheral pulmonary stenosis in three generations of a family: a form of arterial dysplasia. Am. J. Med. Genet. 45: 739-742, 1993. [PubMed: 8456853] [Full Text: https://doi.org/10.1002/ajmg.1320450614]
Lewis, A. J., Ongley, P. A., Kincaid, O. W., Ritter, D. G. Supravalvular aortic stenosis: report of a family with peculiar somatic features and normal intelligence. Dis. Chest 55: 372-379, 1969. [PubMed: 5780776] [Full Text: https://doi.org/10.1378/chest.55.5.372]
Li, D. Y., Toland, A. E., Boak, B. B., Atkinson, D. L., Ensing, G. J., Morris, C. A., Keating, M. T. Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum. Molec. Genet. 6: 1021-1028, 1997. [PubMed: 9215670] [Full Text: https://doi.org/10.1093/hmg/6.7.1021]
Logan, W. F., Jones, E. W., Walker, E., Coulshed, N., Epstein, E. J. Familial supravalvar aortic stenosis. Brit. Heart J. 27: 547-559, 1965. [PubMed: 14324113] [Full Text: https://doi.org/10.1136/hrt.27.4.547]
McCue, C. M., Robertson, L. W., Lester, R. G., Mauck, H. P., Jr. Pulmonary artery coarctations: a report of 20 cases with review of 319 cases from the literature. J. Pediat. 67: 222-238, 1965.
McCue, C. M., Spicuzza, T. J., Robertson, L. W., Mauck, H. P., Jr. Familial supravalvular aortic stenosis. J. Pediat. 73: 889-895, 1968. [PubMed: 5748503] [Full Text: https://doi.org/10.1016/s0022-3476(68)80242-2]
McDonald, A. H., Gerlis, L. M., Sommerville, J. Familial arteriopathy with associated pulmonary and systemic arterial stenosis. Brit. Heart J. 31: 375-385, 1969. [PubMed: 5401816] [Full Text: https://doi.org/10.1136/hrt.31.3.375]
McKusick, V. A. Personal Communication. Baltimore, Md. 1978.
Metcalfe, K., Rucka, A. K., Smoot, L., Hofstadler, G., Tuzler, G., McKeown, P., Siu, V., Rauch, A., Dean, J., Dennis, N., Ellis, I., Reardon, W., Cytrynbaum, C., Osborne, L., Yates, J. R., Read, A. P., Donnai, D., Tassabehji, M. Elastin: mutational spectrum in supravalvular aortic stenosis. Europ. J. Hum. Genet. 8: 955-963, 2000. [PubMed: 11175284] [Full Text: https://doi.org/10.1038/sj.ejhg.5200564]
Micale, L., Turturo, M. G., Fusco, C., Augello, B., Jurado, L. A. P., Izzi, C., Digilio, M. C., Milani, D., Lapi, E., Zelante, L., Merla, G. Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis. Europ. J. Hum. Genet. 18: 317-323, 2010. [PubMed: 19844261] [Full Text: https://doi.org/10.1038/ejhg.2009.181]
Morris, C. A., Loker, J., Ensing, G., Stock, A. D. Supravalvular aortic stenosis cosegregates with a familial 6;7 translocation which disrupts the elastin gene. Am. J. Med. Genet. 46: 737-744, 1993. [PubMed: 8362925] [Full Text: https://doi.org/10.1002/ajmg.1320460634]
Morrison, R. C., McNalley, M. C. The spectrum of abnormalities in supravalvular aortic stenosis. (Abstract) Am. J. Cardiol. 19: 143 only, 1967.
O'Connor, W. N., Davis, J. B., Jr., Geissler, R., Cottrill, C. M., Noonan, J. A., Todd, E. P. Supravalvular aortic stenosis: clinical and pathologic observations in six patients. Arch. Path. Lab. Med. 109: 179-185, 1985. [PubMed: 3838444]
Olson, T. M., Michels, V. V., Lindor, N. M., Pastores, G. M., Weber, J. L., Schaid, D. J., Driscoll, D. J., Feldt, R. H., Thibodeau, S. N. Autosomal dominant supravalvular aortic stenosis: localization to chromosome 7. Hum. Molec. Genet. 2: 869-873, 1993. [PubMed: 8364568] [Full Text: https://doi.org/10.1093/hmg/2.7.869]
Olson, T. M., Michels, V. V., Urban, Z., Csiszar, K., Christiano, A. M., Driscoll, D. J., Feldt, R. H., Boyd, C. D., Thibodeau, S. N. A 30 kb deletion within the elastin gene results in familial supravalvular aortic stenosis. Hum. Molec. Genet. 4: 1677-1679, 1995. [PubMed: 8541862] [Full Text: https://doi.org/10.1093/hmg/4.9.1677]
Page, H. L., Jr., Vogel, J. H. K., Pryor, R., Blount, S. G., Jr. Supravalvular aortic stenosis: unusual observations in three patients. Am. J. Cardiol. 23: 270-277, 1969. [PubMed: 5773126] [Full Text: https://doi.org/10.1016/0002-9149(69)90077-0]
Pastores, G. M., Michels, V. V., Schaid, D. J., Driscoll, D. J., Feldt, R. H., Thibodeau, S. N. Exclusion of calcitonin/alpha-CGRP gene defect in a family with autosomal dominant supravalvular aortic stenosis. J. Med. Genet. 29: 56-57, 1992. [PubMed: 1552547] [Full Text: https://doi.org/10.1136/jmg.29.1.56]
Rowe, R. D. Maternal rubella and pulmonary artery stenoses: report of eleven cases. Pediatrics 32: 180-185, 1963. [PubMed: 14044445]
Schmidt, M. A., Ensing, G. J., Michels, V. V., Carter, G. A., Hagler, D. J., Feldt, R. H. Autosomal dominant supravalvular aortic stenosis: large three-generation family. Am. J. Med. Genet. 32: 384-389, 1989. [PubMed: 2658589] [Full Text: https://doi.org/10.1002/ajmg.1320320324]
Strong, W. B., Perrin, E., Liebman, J., Silbert, D. R. Systemic and pulmonary artery dysplasia associated with unexpected death in infancy. J. Pediat. 77: 233-238, 1970. [PubMed: 5431207] [Full Text: https://doi.org/10.1016/s0022-3476(70)80329-8]
Tassabehji, M., Metcalfe, K., Donnai, D., Hurst, J., Reardon, W., Burch, M., Read, A. P. Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis. Hum. Molec. Genet. 6: 1029-1036, 1997. [PubMed: 9215671] [Full Text: https://doi.org/10.1093/hmg/6.7.1029]
von Dadelszen, P., Chitayat, D., Winsor, E. J. T., Cohen, H., MacDonald, C., Taylor, G., Rose, T., Hornberger, L. K. De novo 46,XX,t(6;7)(q27;q11;23) (sic) associated with severe cardiovascular manifestations characteristic of supravalvular aortic stenosis and Williams syndrome. Am. J. Med. Genet. 90: 270-275, 2000. [PubMed: 10710222] [Full Text: https://doi.org/10.1002/(sici)1096-8628(20000214)90:4<270::aid-ajmg2>3.0.co;2-r]
Williams, J. C., Barratt-Boyes, B. G., Lowe, J. B. Supravalvular aortic stenosis. Circulation 24: 1311-1318, 1961. [PubMed: 14007182] [Full Text: https://doi.org/10.1161/01.cir.24.6.1311]
Wooley, C. F., Hosier, D. M., Booth, R. W., Molnar, W., Sirak, H. D., Ryan, J. M. Supravalvular aortic stenosis: clinical experiences with four patients including familial occurrence. Am. J. Med. 31: 717-725, 1961. [PubMed: 14008275] [Full Text: https://doi.org/10.1016/0002-9343(61)90156-5]