Abstract
Supravalvular aortic stenosis (SVAS) is a localized or diffuse congenital narrowing of the ascending aorta which may occur sporadically, as a familial defect, or in association with Williams syndrome. Familial cases suggest an autosomal dominant gene defect but the underlying molecular basis of SVAS is unknown. In this study, we sought to localize the genetic defect in familial SVAS by linkage analysis in a large three generation family. A total of 44 polymorphic markers were examined for linkage, including 17 Southern blot-based RFLPs, 2 PCR-based RFLPs, and 25 microsatellites, primarily of the (CA)n repeat type. We report linkage of the disease phenotype to a highly informative (CA)n repeat marker, Mfd 50, at locus D7S440 which has been localized to chromosome arm 7q. Using a 100% penetrance model, which was more conservative than lower values of penetrance, a peak LOD score of 4.66 at a recombination frequency of 0.043 was found. A number of candidate genes have been localized to this region, including collagen 1A2, laminin B1, and elastin. Based on our preliminary linkage data, the abnormal microscopic appearance of aortic elastic fibers in SVAS, and analogous animal and human diseases associated with elastic fiber and vascular abnormalities, there is indirect evidence suggesting elastin as a possible candidate gene for this disorder.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 869-873 |
| Number of pages | 5 |
| Journal | Human Molecular Genetics |
| Volume | 2 |
| Issue number | 7 |
| State | Published - Jul 1993 |
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ASJC Scopus subject areas
- Genetics
- Statistics, Probability and Uncertainty
- Applied Mathematics
- Public Health, Environmental and Occupational Health
- Molecular Biology
- Genetics(clinical)
Cite this
Autosomal dominant supravalvular aortic stenosis : Localization to chromosome 7. / Olson, Timothy Mark; Michels, Virginia V.; Lindor, Noralane Morey; Pastores, Gregory M.; Weber, James L.; Schaid, Daniel J; Driscoll, David J.; Feldt, Robert H.; Thibodeau, Stephen N.
In: Human Molecular Genetics, Vol. 2, No. 7, 07.1993, p. 869-873.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Autosomal dominant supravalvular aortic stenosis
T2 - Localization to chromosome 7
AU - Olson, Timothy Mark
AU - Michels, Virginia V.
AU - Lindor, Noralane Morey
AU - Pastores, Gregory M.
AU - Weber, James L.
AU - Schaid, Daniel J
AU - Driscoll, David J.
AU - Feldt, Robert H.
AU - Thibodeau, Stephen N
PY - 1993/7
Y1 - 1993/7
N2 - Supravalvular aortic stenosis (SVAS) is a localized or diffuse congenital narrowing of the ascending aorta which may occur sporadically, as a familial defect, or in association with Williams syndrome. Familial cases suggest an autosomal dominant gene defect but the underlying molecular basis of SVAS is unknown. In this study, we sought to localize the genetic defect in familial SVAS by linkage analysis in a large three generation family. A total of 44 polymorphic markers were examined for linkage, including 17 Southern blot-based RFLPs, 2 PCR-based RFLPs, and 25 microsatellites, primarily of the (CA)n repeat type. We report linkage of the disease phenotype to a highly informative (CA)n repeat marker, Mfd 50, at locus D7S440 which has been localized to chromosome arm 7q. Using a 100% penetrance model, which was more conservative than lower values of penetrance, a peak LOD score of 4.66 at a recombination frequency of 0.043 was found. A number of candidate genes have been localized to this region, including collagen 1A2, laminin B1, and elastin. Based on our preliminary linkage data, the abnormal microscopic appearance of aortic elastic fibers in SVAS, and analogous animal and human diseases associated with elastic fiber and vascular abnormalities, there is indirect evidence suggesting elastin as a possible candidate gene for this disorder.
AB - Supravalvular aortic stenosis (SVAS) is a localized or diffuse congenital narrowing of the ascending aorta which may occur sporadically, as a familial defect, or in association with Williams syndrome. Familial cases suggest an autosomal dominant gene defect but the underlying molecular basis of SVAS is unknown. In this study, we sought to localize the genetic defect in familial SVAS by linkage analysis in a large three generation family. A total of 44 polymorphic markers were examined for linkage, including 17 Southern blot-based RFLPs, 2 PCR-based RFLPs, and 25 microsatellites, primarily of the (CA)n repeat type. We report linkage of the disease phenotype to a highly informative (CA)n repeat marker, Mfd 50, at locus D7S440 which has been localized to chromosome arm 7q. Using a 100% penetrance model, which was more conservative than lower values of penetrance, a peak LOD score of 4.66 at a recombination frequency of 0.043 was found. A number of candidate genes have been localized to this region, including collagen 1A2, laminin B1, and elastin. Based on our preliminary linkage data, the abnormal microscopic appearance of aortic elastic fibers in SVAS, and analogous animal and human diseases associated with elastic fiber and vascular abnormalities, there is indirect evidence suggesting elastin as a possible candidate gene for this disorder.
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M3 - Article
C2 - 8364568
AN - SCOPUS:0027236402
VL - 2
SP - 869
EP - 873
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 7
ER -