title: Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: Segregation, multiplex relative risk, and heritability.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pignatelli
authors.forename: Mark
authors.initials: M
authors.lastname: Lewin
authors.forename: Trang
authors.initials: T
authors.lastname: Ho
authors.forename: Susan
authors.initials: S
authors.lastname: Fernbach
authors.forename: Andres
authors.initials: A
authors.lastname: Menesses
authors.forename: Wilbur
authors.initials: W
authors.lastname: Lam
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: Norman
authors.initials: N
authors.lastname: Kaplan
authors.forename: Paul
authors.initials: P
authors.lastname: Schliekelman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
mesh_terms: D000704:Analysis of Variance; D001021:Aortic Valve / Q000000981:diagnostic imaging; D018376:Cardiovascular Abnormalities / Q000235:genetics*; D002675:Child, Preschool; D004452:Echocardiography; D005190:Family; D005192:Family Health; D005260:Female; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance; D019655:Quantitative Trait, Heritable; D035781:Siblings; D014694:Ventricular Outflow Obstruction / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology