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.

Quantitative Three‐Dimensional Analysis of Embryonic Chick Morphogenesis Via Microcomputed Tomography

“…Although many birth defects have an underlying genetic mutation, the majority of clinical cases are not traceable to a genetic cause (McBride et al, 2005;Clark et al, 2006). Molecular biology based research over the last decade has uncovered numerous transcription factors, signaling networks, and matricellular proteins essential in controlling embryonic morphogenesis (Camenisch et al…”

Late Coarctation Presenters Suffer Chronic Hypertension Resisting to Medicine Treatment

“…Familial cases of CoA, have been reported. Also, genetic investigation in families with children suffering from hypoplastic left heart syndrome (HLHS), Bicuspid Aortic valve (BAov), Left Ventricular Outfl ow Tract (LVOT) abnormalities with aortic valve stenosis and CoA, suggest a strong genetic infl uence, with an estimated recurrence risk in a future pregnancy of greater than 30-fold [11]. Mutations in the NOTCH1 gene have been identifi ed in individuals with LVOT malformations, including CoA [12].…”

Coarctation of the Aorta in the Adult

“…Sporadically it is associated with William Beuren syndrome or Noonan syndrome. Furthermore, there are family clusters with a high prevalence of different left heart obstructive defects including CoA, bicuspid aortic valve, congenital valvular aortic stenosis, and hypoplastic left heart syndrome, (19,20) suggesting an oligogenetic pattern of inheritance in those families.…”