Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: Segregation, multiplex relative risk, and heritability

Kim L. McBride, Ricardo Pignatelli, Mark Lewin, Trang Ho, Susan Fernbach, Andres Menesses, Wilbur Lam, Suzanne M. Leal, Norman Kaplan, Paul Schliekelman, Jeffrey Towbin, John W. Belmont

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Abstract

The left ventricular outflow tract (LVOTO) malformations, aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart (HLH) constitute a mechanistically defined subgroup of congenital heart defects that have substantial evidence for a genetic component. Evidence from echocardiography studies has shown that bicuspid aortic valve (BAV) is found frequently in relatives of children with LVOTO defects. However, formal inheritance analysis has not been performed. We ascertained 124 families by an index case with AVS, COA, or HLH. A total of 413 relatives were enrolled in the study, of which 351 had detailed echocardiography exams for structural heart defects and measurements of a variety of aortic arch, left ventricle, and valve structures. LVOTO malformations were noted in 30 relatives (18 BAV, 5 HLH, 3 COA, and 3 AVS), along with significant congenital heart defects (CHD) in 2 others (32/413; 7.7%). Relative risk for first-degree relatives in this group was 36.9, with a heritability of 0.71-0.90. Formal segregation analysis suggests that one or more minor loci with rare dominant alleles may be operative in a subset of families. Multiplex relative risk analysis, which estimates number of loci, had the highest maximum likelihood score in a model with 2 loci (range of 1-6 in the lod-1 support interval). Heritability of several aortic arch measurements and aortic valve was significant. These data support a complex but most likely oligogenic pattern of inheritance. A combination of linkage and association study designs is likely to enable LVOTO risk gene identification. This data can also provide families with important information for screening asymptomatic relatives for potentially harmful cardiac defects.

Original languageEnglish (US)
Pages (from-to)180-186
Number of pages7
JournalAmerican Journal of Medical Genetics
Volume134 A
Issue number2
DOIs
StatePublished - Apr 15 2005

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Ventricular Outflow Obstruction
Aortic Coarctation
Aortic Valve Stenosis
Congenital Heart Defects
Thoracic Aorta
Echocardiography
Multifactorial Inheritance
Aortic Valve
Heart Ventricles
Alleles

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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Inheritance analysis of congenital left ventricular outflow tract obstruction malformations : Segregation, multiplex relative risk, and heritability. / McBride, Kim L.; Pignatelli, Ricardo; Lewin, Mark; Ho, Trang; Fernbach, Susan; Menesses, Andres; Lam, Wilbur; Leal, Suzanne M.; Kaplan, Norman; Schliekelman, Paul; Towbin, Jeffrey; Belmont, John W.

In: American Journal of Medical Genetics, Vol. 134 A, No. 2, 15.04.2005, p. 180-186.

Research output: Contribution to journalArticle

McBride, KL, Pignatelli, R, Lewin, M, Ho, T, Fernbach, S, Menesses, A, Lam, W, Leal, SM, Kaplan, N, Schliekelman, P, Towbin, J & Belmont, JW 2005, 'Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: Segregation, multiplex relative risk, and heritability', American Journal of Medical Genetics, vol. 134 A, no. 2, pp. 180-186. https://doi.org/10.1002/ajmg.a.30602
McBride, Kim L. ; Pignatelli, Ricardo ; Lewin, Mark ; Ho, Trang ; Fernbach, Susan ; Menesses, Andres ; Lam, Wilbur ; Leal, Suzanne M. ; Kaplan, Norman ; Schliekelman, Paul ; Towbin, Jeffrey ; Belmont, John W. / Inheritance analysis of congenital left ventricular outflow tract obstruction malformations : Segregation, multiplex relative risk, and heritability. In: American Journal of Medical Genetics. 2005 ; Vol. 134 A, No. 2. pp. 180-186.
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AU - Ho, Trang

AU - Fernbach, Susan

AU - Menesses, Andres

AU - Lam, Wilbur

AU - Leal, Suzanne M.

AU - Kaplan, Norman

AU - Schliekelman, Paul

AU - Towbin, Jeffrey

AU - Belmont, John W.

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N2 - The left ventricular outflow tract (LVOTO) malformations, aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart (HLH) constitute a mechanistically defined subgroup of congenital heart defects that have substantial evidence for a genetic component. Evidence from echocardiography studies has shown that bicuspid aortic valve (BAV) is found frequently in relatives of children with LVOTO defects. However, formal inheritance analysis has not been performed. We ascertained 124 families by an index case with AVS, COA, or HLH. A total of 413 relatives were enrolled in the study, of which 351 had detailed echocardiography exams for structural heart defects and measurements of a variety of aortic arch, left ventricle, and valve structures. LVOTO malformations were noted in 30 relatives (18 BAV, 5 HLH, 3 COA, and 3 AVS), along with significant congenital heart defects (CHD) in 2 others (32/413; 7.7%). Relative risk for first-degree relatives in this group was 36.9, with a heritability of 0.71-0.90. Formal segregation analysis suggests that one or more minor loci with rare dominant alleles may be operative in a subset of families. Multiplex relative risk analysis, which estimates number of loci, had the highest maximum likelihood score in a model with 2 loci (range of 1-6 in the lod-1 support interval). Heritability of several aortic arch measurements and aortic valve was significant. These data support a complex but most likely oligogenic pattern of inheritance. A combination of linkage and association study designs is likely to enable LVOTO risk gene identification. This data can also provide families with important information for screening asymptomatic relatives for potentially harmful cardiac defects.

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