These two conditions, which account for 1–2% of all SAR131675 congenital heart disease in humans, are still difficult to treat. Given the fact that NFATC1 is at the center of valve formation in mammals, we hypothesize that mutations in the gene encoding it would be associated with valve malformations in humans. We have previously shown that a tandem repeat in the intronic region of NFATC1 is associated with ventricular septal defects but with no valvular phenotype. We therefore screened for such mutations in patients with different valve diseases registered at the congenital heart disease genetics program at the American University of Beirut Medical Center. Results showed 2 novel missense single nucleotide polymorphisms in only one patient with tricuspid atresia. Functional analyses of the mutated protein do show a defect in its cellular localization, transcriptional activities and DNA binding patterns suggesting that the mutations are disease causing. Congenital heart diseases are still the leading cause of death in newborns in addition to being the most frequent congenital diseases in humans. The genetic mechanisms underlying such diseases however, are being unraveled slowly in the last decade because of the tremendous work done on understanding the molecular mechanisms governing cardiac development in numerous organisms. These mechanisms include the collaborative interaction between transcription factors and their occupancy of conserved cis regulatory elements on different cardiac-specific promoters. Led to the formulation of hypotheses that mutations in these genes could cause heart malformations in humans. More importantly, the available data on genes such as GATA4, NKX2-5 and TBX5 do point to a dose-dependent genotype-phenotype correlation whereby haploinsufficiency is by itself diseases-causing. Our results go along with what is published in that regard by adding the NFATC1 gene to the list of mutated genes linked to congenital heart disease in humans, particularly valve diseases. We have shown two heterozygous mutations on one allele of the NFATC1 gene in one patient with tricuspid atresia out of 19. The fact that the double mutation is also found in the father who has a normal phenotype argues for incomplete penetrance, a phenomenon seen in other genes encoding transcription factors involved in cardiac and non-cardiac congenital diseases. One such example is the Arg25Cys mutation, which was shown to abrogate the transcriptional activity of the NKX2-5 protein and yet has reduced penetrance depending on the population study groups. In mice, the Holt-Oram syndrome recreated with the heterozygous Tbx5 model is the best example of a dosage dependent phenotype-genotype correlation. In fact, null mice for both Tbx5 alleles showed a very severe cardiac phenotype leading to early embryonic lethality, while mice carrying only one Tbx5 allele display a spectrum of phenotypes recapitulating the ones observed in humans. Unfortunately, in our case the indexedpatient was evaluated for the first time at the age of 16 years at our center when he presented with severe cyanosis and complications of his condition which was not well taken care of at earlier stages and had led to the his death few days after his admission to the hospital. Exon by exon sequencing of different genes encoding transcription factors, including GATA4,5,6, TBX5,20, NKX2-5, PITX2, and NFATC1 was carried out on the whole family and none except NFATC1 showed polymorphisms that could be disease causing. We cannot exclude however, that other not tested gene could also be mutated and carried on the maternally inherited allele, and that the combination of such mutations is responsible for the observed phenotype.