The majority of studies support a relationship between consanguineous parentage and congenital heart disease ( and ). However, it is important that the conclusions drawn from each study are viewed in the light of their respective strengths and limitations. Many studies used a case-control design and included cases of CHD diagnosed by methods such as echocardiography and excluded cases with known chromosome abnormalities or multiple congenital abnormalities. These studies can identify reasonably large numbers to study, however the analyses of cases and controls are critical. A few important points need to be considered: First, to what extent could confounding play a role in differences between case and control groups? Could the choice of certain cases or controls inadvertently lead to elevated or deflated effect sizes that are attributed to consanguinity? Many of these studies used controls from the same hospital or from the geographic region as the cases to minimize potential confounders. Second, how was consanguinity defined and determined? Most studies determined consanguinity considering at least first and second cousin unions, although some studies failed to indicate how consanguinity had been defined. The history of consanguinity also relied largely on the report by the parent of a child with congenital heart disease. Given this commonly used technique, it is important to minimize the possibility of reporting bias in eliciting the history of consanguinity to ensure that the investigation for consanguinity is equally efficient in cases and controls. A majority of the studies attempted to exclude syndromic cases of CHD by excluding chromosome abnormalities and/or suspected syndromes. It is, however, possible that syndromic cases may have been missed due to limited genetic examinations or limitations of record review. Details such as the presence or absence of these variables are important considerations when drawing conclusions from studies (Supplementary Table I See Supporting Information online
Despite these potential issues, most studies conclude that certain lesions such as septal defects are increased in incidence in the setting of consanguinity. Whether less common heart lesions follow a similar pattern is unclear. Population-based studies that capture large numbers of lesions and that quantify relatedness will be helpful [Oyen et al. 2009
Counseling families with consanguinity and congenital heart disease is often performed as for other multifactorial conditions. In the absence of a recognizable pattern of disease inheritance, families are presented with an empiric risk for congenital heart disease based on population data that may or may not take into account the type of heart lesion. This risk may be modified depending on the individual family history and other clinical risk indicators, and may be further adjusted due to the presence of consanguinity, although the degree of risk used in counseling has been variable [Bennett et al. 1999
]. Recurrence risks for non-syndromic CHD often range from 2–6% in the absence of an extended family history of CHD [Boughman et al. 1987
; Calcagni et al. 2007
; Gill et al. 2003
; Harper 2004
]. Based on our review of these studies, we recognize that future large population-based studies of birth defects such as congenital heart diseases should incorporate measures of genetic relatedness into their assessment and analysis, and recurrence of disease should be tracked.
Since it is uncommon for isolated congenital heart disease to be inherited in a classic Mendelian manner, most cases are assumed to be complex. For such multifactorial diseases, the ability to discuss and present precise risks to a concerned family is directly related to our understanding of the basis of disease. Based on the studies reviewed here, which are the best currently available, we still need to strive to understand the relative contribution of genetics versus the environment in congenital heart disease. If we can determine the proportional effect of consanguinity on disease, this may help determine the genetic contribution to a specific complex condition or the comparative role of genetics versus environmental influences.
As the effect of consanguinity on the risk of congenital heart disease decreases, one would hypothesize that there could be potentially a larger number of low-effect genes involved in the disease (or less of a genetic contribution) and more potential environmental contribution. Indeed, environmental factors such as blood flow are clearly important in early heart development, yet its contribution is difficult to assess in current human studies. Furthermore, if teratogens [Lammer et al. 1985
; Malik et al. 2008
] such as rubella or alcohol can contribute to the risk of congenital heart disease, there is clearly a role for understanding how the environmental influences lead to disease [Jenkins et al. 2007
] given a susceptible genetic background.
The current discussion on consanguinity and risk for congenital heart disease is timely given the possibility for future more informative studies. With enormous growth in the ability to genotype individuals based on detection of single nucleotide polymorphisms (SNPs), we now can determine the ethnic ancestry of an individual based on genetics alone, and the application of next generation methodologies will greatly increase this analytical capacity. Such genomic identity may be able to more precisely estimate the degree of genetic relatedness and identify consanguineous relationships that otherwise could have been missed or miscategorized based on self-report.
Genome-scale SNP identification has also identified regions of extended loss of heterozygosity in normal individuals, which could result from past consanguinity [Broman et al. 1999
; Gibson et al. 2006
; Nalls et al. 2009
], and further studies are needed to elucidate the role of these regions in disease. The volume of genetic information available is rapidly expanding and the technology is available to sequence entire exomes or genomes for detection of SNPs or small copy number variants that could influence disease. These types of studies will reveal potentially common or rare variants associated with disease, and it will be possible to assess the role of these predisposing factors in the setting of consanguineous families.
The influence of de novo
changes on oligogenic disease is also unknown, however it is possible that these genomic alterations combined with the effects of consanguinity could bring together the requisite components for disease. Furthermore, the epigenetic factors that contribute to CHD are largely unknown [Shieh et al. 2009
], and it is unclear if consanguinity results in shared environmental contributions to disease. Different populations may be differentially susceptible to genetic and environmental perturbations, and it is important to continue these studies with a global perspective.
If we can develop a better understanding of the relationship between consanguinity and congenital heart disease, we can implement more accurate genetic counseling and more effective clinical management. We propose emphasis in four key areas: (1) With patients involved in consanguineous unions, to discuss potential implications on health based on the family history and clinical assessment. A consanguineous union may result in a greater risk for congenital heart disease based on studies presented in the literature, but the bias towards publication of positive findings merits consideration, and the magnitude of risk should be taken in context of the individual history and other potential indicators of disease. (2) Continue to educate healthcare providers and patients about the importance of the medical family history. (3) Promote a balanced understanding of consanguinity and develop patient skills to effectively manage familial health risks. (4) Prioritize disease prevention and investigation into genetic predispositions to disease and integrate cultural issues such as consanguinity into global health initiatives.