Review
The genetics of cardiac birth defects

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Abstract

Congenital heart disease likely results from a complex mixture of environmental and genetic factors. Recent work has elucidated rare single gene mutations that cause a variety of cardiac defects, but the etiologies of more common disease remains unknown. Here, we review the known genetic causes of cardiac malformations and discuss future approaches for addressing sporadic congenital heart disease as a complex trait.

Introduction

The heart is the first organ to form in the embryo and begins to pump blood by 3 weeks of gestation when adequate nutrients and oxygen can no longer be provided to the developing fetus by simple diffusion. Cardiogenesis is a complex process involving multiple cell types and appears to be highly susceptible to perturbations, which result in malformations of the heart. In humans, the resulting congenital cardiovascular malformations (CCVM) have been reported to occur in approximately 8 out of every 1000 live births [1], but this is likely an underestimate. The most common form of CCVM, bicuspid aortic valve (BAV) is present in about 1–2% of all neonates, but is generally excluded from estimates of CCVM since it is asymptomatic in childhood. However, BAV often causes significant heart disease later in life [2]. Overall, CCVM remains the leading non-infectious cause of mortality in the first year of life [3].

Despite these statistics, advances in neonatal diagnosis and surgery in the past few decades have reduced the morbidity and mortality for many CCVM [4]. As a result, an increasing number of survivors are reaching child-bearing age and may be at risk for transmitting disease at a higher frequency than the general population. A better understanding of the molecular and genetic mechanisms involved in cardiogenesis and CCVM could lead to future diagnostics aimed at identifying populations at greater risk for having offspring with CCVM and ultimately towards therapies to prevent the occurrence of CCVM.

Section snippets

Critical events in cardiogenesis as they relate to disease

Here we will provide a brief review of cardiac morphogenesis focusing on its relationship to disease. A more complete review of heart development can be found in recent reviews [5], [6], [7]. Clinical reference books will provide a more thorough description and visualization of the CCVM described [8].

Genetic etiologies of syndromic CCVM

Due to the multifactoral nature of the disease, the etiologies of CCVM are largely unknown. There are known environmental components, which have been revealed from the increased risk of CCVM when a fetus is exposed to teratogens, such as alcohol or anti-epileptic drugs early in pregnancy [18], [19]. Over the past decade, a number of single gene mutations that cause many forms of CCVM have revealed a significant genetic contribution as well. Many of these highly informative mutations were

Genetic etiologies of isolated CCVM

While these syndromes have helped elucidate some of the mechanisms of CCVM, the majority of CCVM occurs in isolation of any other organ malformation. There have been cases reported where mutations in TBX5 and JAG1 cause non-syndromic CCVM [27], [46] but they are rare. Since 1998, a small number of genes have been linked to CCVM by performing linkage analysis on large families that have a clinical history consistent with autosomal dominant inheritance. The genes discussed hereafter have a clear

Genetic risk factors for sporadic CCVM

Even though these families have provided clear evidence that single genes can cause isolated CCVM, most cases of CCVM are sporadic, in that there is no immediate family history. Recent work suggests that most of these sporadic CCVM are multifactorial with no single gene being totally responsible [60]. As work with NKX2.5 suggests, some of these sporadic cases will be due in part to mutations in NOTCH1, JAGGED1, GATA4, MHC6, or TBX5, but each will probably account for less than 5% of CCVM [27],

Future directions

Over the past decade, it has become increasingly accepted that genetic variations and mutations play a major role in the development of CCVM. The genes that have been implicated in syndromic and familial non-syndromic CCVM have also been shown to be mutated in cases of sporadic CCVM, albeit uncommonly. Despite the successes thus far, because of the scarcity of pedigrees that lend themselves to forward genetic screens, new approaches will probably have to be taken to discover the causes of

Acknowledgements

The authors would like to thank K. Cordes and J. Shieh for suggestions and editing. This work was supported by grants from NHLBI/NIH and the March of Dimes. DS is an Established Investigator of the American Heart Association.

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