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Hypoplastic left heart syndrome is heritable
Robert B Hinton1, Lisa J Martin, Meredith E Tabangin
1Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Insights
Genetic factors largely determine hypoplastic left heart syndrome (HLHS), a severe congenital heart defect. This study found high heritability for HLHS and associated cardiovascular malformations in affected families.
Area of Science:
- Cardiovascular Genetics
- Pediatric Cardiology
- Congenital Heart Defects
Background:
- Hypoplastic left heart syndrome (HLHS) is a critical congenital cardiovascular malformation (CVM) causing significant infant mortality and morbidity.
- Observed familial clustering of HLHS and bicuspid aortic valve (BAV) suggests a genetic component, though its significance remains unclear.
Purpose of the Study:
- To quantify the genetic contribution (heritability) to HLHS in families with an HLHS proband.
- To investigate the heritability of HLHS and associated CVMs.
Main Methods:
- A 3-generation family history was collected from 38 HLHS probands.
- Echocardiograms were performed on 235 family members to assess for CVM.
- Heritability (h2) was estimated using maximum-likelihood-based variance decomposition.
Main Results:
- High heritability for HLHS (99%) and HLHS with associated CVM (74%) was observed (p < 0.00001).
- 55% of families had multiple affected individuals; 36% of participants had CVM, including 11% with BAV.
- Sibling recurrence risk for HLHS was 8% and for CVM was 22%.
Conclusions:
- The high heritability strongly indicates that genetic factors are the primary determinants of HLHS.
- HLHS appears to be a severe manifestation of valve malformation, evidenced by frequent valve dysplasia in probands and increased BAV prevalence in relatives.
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.
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