Exploring genetic variability in FOXE1 through in silico approaches: new insights on UTR variants

Abstract

<title>Abstract</title> The <italic>FOXE1</italic> gene is a transcription factor critical for thyroid development and function, and has been associated with thyroid disorders and other phenotypic traits like cancer and orofacial clefts. This study explores the genetic variability in <italic>FOXE1</italic> , focusing on non-synonymous single nucleotide variants (nsSNVs) and untranslated region (UTR) variants, using <italic>in silico</italic> approaches to assess their functional and structural impacts. A total of 1,003 variants were retrieved from the Genome Browser, including 306 nsSNVs and 508 UTR variants. After analysis with the Variant Effect Predictor and eight additional prediction tools, 37 high-risk variants were identified. Of these, 23 variants led to smaller mutant amino acids, 13 to larger substitutions, and 1 had no size-related change. Structural predictions showed altered hydrophobicity and torsion angles in several variants, with a suggestion of significant functional consequences. Decreased stability observed in 32 high-risk variants, indicating potential disruptions to protein function. Additionally, UTR variants rs41274262 and rs7043516, were predicted to increase regulatory activity slightly. Frequency analysis demonstrated considerable variability in the prevalence of these variants across different populations, with some high-risk variants showing higher frequencies in African and East Asian populations. Furthermore, associations with clinical phenotypes, including thyroid hypoplasia, congenital hypothyroidism, and orofacial clefts, were noted for specific variants. Conservation analysis revealed that several UTR variants are highly conserved across species, suggesting potential functional roles in humans. This study provides comprehensive insights into the structural, functional, and regulatory impacts of genetic variation in the <italic>FOXE1</italic> gene and its relevance to human health.