Clinical Research
Congenital Heart Disease
Hypoplastic Left Heart Syndrome Is Heritable

https://doi.org/10.1016/j.jacc.2007.07.021Get rights and content
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Objectives

This study sought to determine the size of the genetic effect (heritability) in families identified by a hypoplastic left heart syndrome (HLHS) proband.

Background

Hypoplastic left heart syndrome is a severe form of cardiovascular malformation (CVM), and it remains a leading cause of infant mortality and childhood morbidity. Familial clustering of HLHS and bicuspid aortic valve (BAV) has been observed, and pedigree analysis has suggested recessive inheritance. The genetic significance of these observations is unknown.

Methods

In 38 probands with HLHS, a 3-generation family history was obtained; using a sequential sampling strategy, echocardiograms on family members were performed. A total of 235 participants were recruited. Heritability (h2) of HLHS and associated CVM was estimated using maximum-likelihood-based variance decomposition.

Results

All HLHS probands had aortic valve hypoplasia and dysplasia; dysplasia of the mitral (94%), tricuspid (56%), and pulmonary (11%) valves was also noted. Overall, 21 of 38 (55%) families had more than 1 affected individual, and 36% of participants had CVM, including 11% with BAV. The heritability of HLHS alone and with associated CVM were 99% and 74% (p < 0.00001), respectively. The sibling recurrence risk for HLHS was 8%, and for CVM was 22%.

Conclusions

The high heritability of HLHS suggests that it is determined largely by genetic factors. The frequent occurrence of left- and right-sided valve dysplasia in HLHS probands and the increased prevalence of BAV in family members suggests that HLHS is a severe form of valve malformation.

Abbreviations and Acronyms

BAV
bicuspid aortic valve
CI
confidence interval
CVM
cardiovascular malformation
HLHS
hypoplastic left heart syndrome
SOLAR
Sequential Oligogenic Linkage Analysis Routines

Cited by (0)

Supported by a Trustee Award from Children’s Hospital Research Foundation (to Dr. Hinton), Cincinnati, Ohio, and grants from the National Institutes of Health HD43005 (to Dr. Hinton), HL085122 (to Dr. Hinton), MH059490 (for Sequential Oliogogenic Linkage Analysis Routines software package, San Antonio, Texas), HL069712 (to Dr. Benson), and HL074728 (to Drs. Martin, Cripe, and Benson), Bethesda, Maryland.