Genome-wide linkage analysis of congenital heart defects using MOD score analysis identifies two novel loci

Background: Congenital heart defects (CHD) is the most common cause
of death from a congenital structure abnormality in newborns and is
often associated with fetal loss. There are many types of CHD.
Human genetic studies have identified genes that are responsible
for the inheritance of a particular type of CHD and for some types
of CHD previously thought to be sporadic. However, occasionally
different members of the same family might have anatomically
distinct defects - for instance, one member with atrial septal
defect, one with tetralogy of Fallot, and one with ventricular
septal defect. Our objective is to identify susceptibility loci for
CHD in families affected by distinct defects. The occurrence of
these apparently discordant clinical phenotypes within one family
might hint at a genetic framework common to most types of CHD.
Results: We performed a genome-wide linkage analysis using MOD
score analysis in families with diverse CHD. Significant linkage
was obtained in two regions, at chromosome 15 (15q26.3, P-empirical
= 0.0004) and at chromosome 18 (18q21.2, P-empirical = 0.0005).
Conclusions: In these two novel regions four candidate genes are
located: SELS, SNRPA1, and PCSK6 on 15q26.3, and TCF4 on 18q21.2.
The new loci reported here have not previously been described in
connection with CHD. Although further studies in other cohorts are
needed to confirm these findings, the results presented here
together with recent insight into how the heart normally develops
will improve the understanding of CHD.