Rare pathogenic NR2F2 (COUP-TFII) variants as potential etiological causes in pediatric patients with congenital...

Congenital heart diseases (CHDs) are complex genetic disorders, and their genetic basis is not yet fully understood. Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TFII) encodes a transcription factor which is expressed at high levels during mammalian development. Few studies have identified heterozygous and rare variants in the NR2F2 gene in individuals with CHD. This study aimed to evaluate the association between pathogenic genetic alterations in NR2F2 with CHD risk.

A case-control study was conducted on a group of 135 patients (83 boys and 52 girls) with various types of non-hereditary, isolated CHD who were undergoing open-heart surgery. Additionally, 95 matched healthy children without syndromic or isolated heart abnormalities were selected.

Using Sanger sequencing, we identified 5 heterozygous single nucleotide variants in exons 2 and 3 of the NR2F2 gene. These variations were novel and not present in any genomic variation databases. Four of the variations were missense mutations (p.Pro159Arg, p.Ser329Phe, p.Qln338Pro, and p.Tyr348Ser) and one was a synonymous variant (p.G361 = ) in the coding region. Importantly, in silico results indicated that the missense variants had pathogenic effects on protein function. Additionally, the missense variants substantially altered the predicted structure of COUP-TFII.

The results we obtained not only validate the correlation between NR2F2 mutations and CHDs but also have significant potential for guiding new preventive and therapeutic strategies. This could contribute to the advancement of medical interventions in the fields of cardiology and genetics.