The role of ESCO2, SALL4 and TBX5 genes in the susceptibility to thalidomide teratogenesis

Abstract

Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide afects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verifed how thalidomide afect them in human pluripotent stem cells (hPSCs) through a diferential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identifed 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were signifcantly diferent (p<0.05). Eleven variants in SALL4 and TBX5 were previously associated with cardiac diseases or malformations; however, in TE sample there was no association. Variant efect prediction tools showed 97% of the variants with potential to infuence in these genes regulation. DGE analysis showed a signifcant reduction of ESCO2 in hPSCs after thalidomide exposure.