ABSTRACT
Congenital heart defects (CHDs) are the most common type of birth defects and the leading cause of death in infants under 1 year of age, representing a considerable burden of personal suffering and societal cost.
Despite the remarkable progress of the past decade, the aetiology for the majority of cases of CHD remains unknown.
Numerous epidemiologic studies have established the heritable nature of CHDs (). Experimental studies in animal model, of heart development has led to the identification of a network of evolutionarily conserved cardiac transcription factors (TFs) that regulate each other's expression in order to stabilize and reinforce the cardiac gene program.
Over the past years, human genetic studies have identified that several syndromic and familial cases of CHD are cause by single gene mutations in cardiac TFs. However, the frequency of germline mutations in TFs of sporadic CHD seems to be low ranging from 0 to about 3%. Therefore, the fundamental aetiology of more common “sporadic” form of CHD remains unknown and there is a strong need to investigate the fundamental pathogenic mechanisms of CHD.
The aim of the study is to verify the presence of germline and somatic mutation in two TFs, GATA4 and NKX2.5 in patients with familial or sporadic CHD.
We performed a direct sequencing of GATA4 and NKX2.5 in 10 patients affected by CHD: 5 familiar (2 male; 24 months ± 36) and 5 sporadic cases (1 male; 35 months ± 67) of CHD.
We collected blood samples from familial patients. Bioptic cardiac were also collected from sporadic patients who underwent cardiac surgery.
We investigated the genomic DNA for sequence variations in the entire coding region and untranslated regions (3'-UTR) of GATA4. We identified a non synonymous mutation in exon 6 in 2 familial cases (c.1130 a>g;
p.Ser377Gly) and a genetic polymorphism in exon 1 (c.-543 c>t) in 4 familial () cases and in 2 sporadic cases ().
We also found several genetic polymorphisms in both group of patients in intronic regions of genes (+5 g>a; -64 g>c; +52 t>a; -202 c>t; -174 t>c;
+56 c>a).
Finally, we also identified a new genetic variant in 3’UTR region of GATA gene in only 2 familial cases (+852 g>a).
However, genetic screening in 50 healthy subjects (54 males; 47 years ± 16) has also showed the presence of the same genetic variant with an allele frequency of %in the general population.
In NKX2.5 gene we did not identify any novel mutation.
In conclusion, our study identified only common variants without any novel pathological mutations.
These findings support the hypothesis that other molecular mechanisms (epigenetics) may be involved in the pathogenesis of CHD.
Further studies are needs to better understanding the aetiology of CHD and hopefully result in improved genetic counselling and care of affected individuals and their families.
