TY - JOUR
T1 - Autosomal dominant supravalvular aortic stenosis
T2 - Localization to chromosome 7
AU - Olson, Timothy M.
AU - Michels, Virginia V.
AU - Lindor, Noralane M.
AU - Pastores, Gregory M.
AU - Weber, James L.
AU - Schaid, Daniel J.
AU - Driscoll, David J.
AU - Feldt, Robert H.
AU - Thibodeau, Stephen N.
N1 - Funding Information:
This study was supported by a grant from the Minnesota chapter of the American Heart Association and by NIH grant HGO0248 to J.L.W.
PY - 1993/7
Y1 - 1993/7
N2 - Supravalvular aortic stenosis (SVAS) is a locallzed or diffuse congenital narrowing of the ascending aorta which may occur sporadically, as a famillal 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 famllial 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, primarilly 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 locallzed or diffuse congenital narrowing of the ascending aorta which may occur sporadically, as a famillal 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 famllial 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, primarilly 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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U2 - 10.1093/hmg/2.7.869
DO - 10.1093/hmg/2.7.869
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 -