Autosomal dominant supravalvular aortic stenosis: Localization to chromosome 7

Timothy Mark Olson, Virginia V. Michels, Noralane Morey Lindor, Gregory M. Pastores, James L. Weber, Daniel J Schaid, David J. Driscoll, Robert H. Feldt, Stephen N Thibodeau

Research output: Contribution to journalArticle

50 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)869-873
Number of pages5
JournalHuman Molecular Genetics
Volume2
Issue number7
StatePublished - Jul 1993

Fingerprint

Aortic Stenosis
Supravalvular Aortic Stenosis
Chromosomes, Human, Pair 7
Chromosomes
Chromosome
Elastin
Genes
Linkage
Defects
Elastic Tissue
Penetrance
Gene
Restriction Fragment Length Polymorphisms
Fibers
Fiber
Williams Syndrome
Linkage Analysis
Microsatellites
Collagen
Dominant Genes

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 journalArticle

Olson, TM, Michels, VV, Lindor, NM, Pastores, GM, Weber, JL, Schaid, DJ, Driscoll, DJ, Feldt, RH & Thibodeau, SN 1993, 'Autosomal dominant supravalvular aortic stenosis: Localization to chromosome 7', Human Molecular Genetics, vol. 2, no. 7, pp. 869-873.
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. / Autosomal dominant supravalvular aortic stenosis : Localization to chromosome 7. In: Human Molecular Genetics. 1993 ; Vol. 2, No. 7. pp. 869-873.
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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.",
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