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CLINICAL RESEARCH: CONGENITAL HEART DISEASE

Hypoplastic Left Heart Syndrome Is Heritable

Robert B. Hinton, Jr, MD^_*,_*, Lisa J. Martin, PhD, Meredith E. Tabangin, MPH, Mjaye L. Mazwi, MD^_*, Linda H. Cripe, MD^_* and D. Woodrow Benson, MD, PhD^_*

^_* Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Manuscript received April 4, 2007; revised manuscript received June 28, 2007, accepted July 1, 2007.

^_* Reprint requests and correspondence: Dr. D. Woodrow Benson, Division of Cardiology, MLC 7042, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039. (Email: Woody.Benson{at}cchmc.org).

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

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