Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve. J Am Coll Cardiol 2009 Mar 24;53(12):1065-71
Date
03/21/2009Pubmed ID
19298921Pubmed Central ID
PMC2703749DOI
10.1016/j.jacc.2008.12.023Scopus ID
2-s2.0-61949160625 (requires institutional sign-in at Scopus site) 120 CitationsAbstract
OBJECTIVES: This study was designed to identify disease loci for hypoplastic left heart syndrome (HLHS) and evaluate the genetic relationship between HLHS and bicuspid aortic valve (BAV).
BACKGROUND: Previously, we identified that HLHS and BAV exhibit complex inheritance, and both HLHS and BAV kindreds are enriched for BAV. However, the genetic basis of HLHS and its relationship to BAV remains unclear.
METHODS: Family-based nonparametric genome-wide linkage analysis was performed in kindreds ascertained by either an HLHS or BAV proband. Echocardiograms were performed on 1,013 participants using a sequential sampling strategy (33 HLHS kindreds, 102 BAV kindreds).
RESULTS: The recurrence risk ratio of BAV in HLHS families (8.05) was nearly identical to that in BAV families (8.77). Linkage to chromosomal regions 10q22 and 6q23 with maximum logarithm of odds scores of 3.2 and 3.1, respectively, was identified in HLHS kindreds. In addition, 5 suggestive loci were identified (7q31, 11q22, 12q13, 14q23, and 20q11). We previously identified loci at chromosomes 18q22, 13q34, and 5q21 in BAV kindreds. The relationship between these loci was examined in the combined HLHS and BAV cohort and associations between loci were demonstrated (5q21, 13q34, and 14q23; 6q23 and 10q22; 7q31 and 20q11). Subsequent subsets linkage analysis showed a significant improvement in the logarithm of odds score at 14q23 only (4.1, p < 0.0001).
CONCLUSIONS: These studies demonstrate linkage to multiple loci identifying HLHS as genetically heterogeneous. Subsets linkage analyses and recurrence risk ratios in a combined cohort provide evidence that some HLHS and BAV are genetically related.
Author List
Hinton RB, Martin LJ, Rame-Gowda S, Tabangin ME, Cripe LH, Benson DWMESH terms used to index this publication - Major topics in bold
Aortic ValveChromosome Mapping
Chromosomes, Human, Pair 10
Chromosomes, Human, Pair 6
Echocardiography
Female
Genetic Heterogeneity
Humans
Hypoplastic Left Heart Syndrome
Inheritance Patterns
Lod Score
Male
Odds Ratio
Pedigree
Phenotype
Statistics, Nonparametric