Congenital heart defects (CHD) refer to abnormalities in the heart structure or function that arise at the fetal stages and affect approximately 1% of newborns . Multiple surgeries are almost always required to correct many of the anatomical defects, and quality of life is often greatly compromised. There are many types of CHD. Examples include transposition of the great arteries/vessels (TGA/TGV), tetralogy of Fallot (TOF), double outlet right ventricle (DORV), atrial septal defects (ASD), ventricular septal defects (VSD), bicuspid aortic valve (BAV), and Ebstein’s anomaly, among many others.
Normal heart development involves many regulatory pathways including receptor-ligand interactions (JAGGED/NOTCH, TGFB-BMP/TGFBR, VEGF/FLT1-FLK1, NODAL/ACVRA-ACVRB and RTK/RAS), signal transduction (kinases or phosphatases such as MAPK, ERK1/2, calcineurin, or GSK), and transcription factors that determine the expression of cardio-specific genes (protein families with a T-box domain TBX1, TBX5, and TBX20, the GATA family GATA4 and FOG2 or homeobox domain NKX2.5 and NKX2.6). Mutations that show a greater penetrance and that therefore approximate a monogenic inheritance are those affecting transcription factors or genes transcribed by them .
Although the major underlying defects that cause CHD are thought to be mutations in regulators of heart development during embryogenesis, epidemiological data also indicate an environmental influence [2–4]. However, these epidemiological studies mostly suggest risk factors rather than underlying disease mechanisms. Genetic factors for some of the CHD include Mendelian mutations, copy number variants, translocations, and single nucleotide polymorphisms (SNPs) [5–7].
A genetic component of CHD diseases was initially implicated by recurrence in families, and by studies showing a co-segregation of CHD with the deletion 22q11.2 . It has also been shown that individuals with an affected parent are at twofold greater risk, which is even greater if siblings are affected . While many studies have investigated the role of genes in the etiology of inherited and sporadic CHD [10–14] these studies have been focusing on specific cardiac lesions separately. Recently, rare variants have also been reported to be associated with CHD . These rare variants are usually present in less than 1% of the normal population but are overrepresented in selected patients. They are typically inherited from an asymptomatic parent and are therefore not believed to be a sufficient cause of CHD in these patients; other mutations need to be present to lead to CHD.
However, occasionally, different members of one family are observed to suffer from anatomically distinct defects — for example, one member with ASD, one with TOF, and one with VSD. These apparently discordant clinical phenotypes arising within one family are difficult to rationalize. Benson et al. observed a coinheritance of different NKX2.5 mutations, i.e., compound heterozygotes, in members of families with ASD, VSD, and cardiac conduction abnormalities, suggesting that mutations in the same gene can affect different parts of the heart, and therefore cause different types of CHD. McGregor et al. reported a statistically significant linkage evidence for a locus on chromosome 14 (within the HOMEZ gene) in South Indian cases born to consanguineous parents. However, the linkage finding was not robust in a genetic association follow-up study in a general United States population. Despite the successes over the past few years, much remains unknown about the genetics of CHD. It is believed that much of the missing heritability is likely to be due to rare variants with larger effect sizes as well as epigenetic effects. Their systematic characterization is beyond the means of studies that currently rely on linkage disequilibrium (LD) patterns such as genome-wide association analysis. In such situations taking family information into consideration using a direct mapping approach complemented by segregation techniques will be a useful strategy. For complex diseases linkage analysis is a powerful method for detecting gene effects [18, 19]. Especially when looking at rare variants, linkage has the advantage over association of not being prone to allelic heterogeneity. That is, the combination of many weak association signals obtained in a certain region for single variants by means of collapsing methods is automatically performed in the context of linkage analysis.
In this study we performed a detailed genome-wide linkage analysis using MOD scores and 6 families affected by different CHD to test for a common genetic background among different types of heart defects.