“Genetic Underpinnings of Isolated Hypoplastic Left Heart”

Doctor's Name: 
Lisa Martin, PhD
Doctor's Name 2: 
D. Woodrow, Benson, PhD
Children's Hospital of Cincinnati

Hypoplastic left heart syndrome (HLHS) is a rare and life-threatening form of congenital heart malformation. HLHS features include an underdevelopment of the left side of the heart; that is, the main pumping chamber (left ventricle) and main artery to body (aorta) are very small. While HLHS was once lethal, a three staged surgical procedure has dramatically improved survival. However, despite improvements in clinical care, little is known of the cause of HLHS. This lack of knowledge has been a barrier to understanding who will have HLHS and what type of clinical outcome can be expected. In addition, parents of children with HLHS want to know their risk of having other affected children, and survivors of HLHS surgical intervention who are now reaching child-bearing age want to know their risk of having children with HLHS.

HLHS recurs in families and some relatives have other types of congenital heart malformation. In previous studies, we showed that HLHS is determined largely by genetic factors. Based on familial inheritance, it has been speculated that HLHS is a recessive form (2 abnormal gene copies) of cardiac malformation, with heterozygotes (one abnormal gene copy) exhibiting less severe malformations. In this case, it would be expected that children with HLHS would frequently have first degree relatives (parents or siblings) with congenital heart malformations. However, in our echocardiographic studies of families, we found other congenital heart malformations in only 40% of other family members. Hence, ~60% of our HLHS cases are isolated, suggesting that semi-dominant inheritance is not likely for these isolated cases, but rather due to recessive or de novo variants.  Since the impact of each of these mechanisms on recurrence risk is dramatically different, determining the underlying genetic cause is essential for improved risk prediction.

Our long-term goal is to lessen the impact of HLHS on patients and their families by expanding our knowledge of underlying cause – an essential step to improving risk prediction.  As a first step, our objective is to identify genetic variants contributing to isolated HLHS.   Our central hypothesis is that isolated HLHS is caused by large genetic variants that alter chromosomal structure (Aim 1) and/or small genetic variants that alter protein coding of a single gene (Aim 2).  To test this hypothesis we will use our family based cohort which is well phenotyped (all participants have had an echocardiographic exam) and genetically evaluate 27 trios (27 HLHS cases and 54 unaffected parents). We will validate findings in our remaining HLHS cases to accomplish two Specific Aims:

Specific Aim 1. Identify structural variants which contribute to isolated HLHS. We will use a high density genotyping chip to assess copy number variants in trios. Genetic models of inheritance assuming recessive and de novo variants will be evaluated to identify candidate CNV. Variants will be prioritized based on genes implicated in heart and valve development and confirmed using follow up genotyping.  The generalizability of these variants will be evaluated in independent HLHS probands.   

Specific Aim2.  Identify sequence variants in isolated HLHS.  To identify sequence variation in HLHS we will use whole exome sequencing in trios.  Genetic models of inheritance assuming recessive and de novo variants will be evaluated to identify candidate protein coding variants.  Sequence variants will be prioritized based putative functionality and on the genes implicated in heart and valve development.  Prioritized variants will be confirmed using follow up genotyping. The presence of these variants in independent probands will be evaluated.

Assessment of both large (structural DNA) and small (single gene sequence alterations) of small well defined families has been a powerful approach for understanding the genetic underpinnings of rare conditions. Thus, we are confident that this pilot project will be successful in identifying strong candidate genetic variants for HLHS.  We anticipate our findings will have substantial impact on recurrence risk assessment for HLHS.  While findings of the proposed pilot studies could provide significant knowledge to aid in reproductive decision making for family members or lead to innovative approaches to the care of HLHS patients, the real value is to provide essential pilot data to support application for a larger grant to study this important question on a bigger scale. By identifying the genetic cause for isolated HLHS, these results will serve to characterize similarities and differences between isolated and familial HLHS and better define the underlying genetic cause of this life threatening birth defect.

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