Genetic evaluation of HAND2 gene and its effects on thalidomide embryopathy

Birth Defects Res. 2022 Dec 1;114(20):1354-1363. doi: 10.1002/bdr2.2092. Epub 2022 Sep 30.


Background: HAND2 is a transcription factor important for embryonic development, required for limbs and cardiovascular development. Thalidomide is a drug responsible to a spectrum of congenital anomalies known as Thalidomide Embryopathy (TE), which includes mainly limb and heart defects. It is known that HAND2 interaction with TBX5, an important protein for limbs and heart development, is inhibited by Thalidomide. The aim of this study was to evaluate and characterize HAND2 in the context of TE, and to evaluate its variability in TE individuals.

Methods: DNA from 35 TE subjects was extracted from saliva samples and PCR was performed for amplification and Sanger sequencing of HAND2 coding sequence.

Results: The analysis showed only one variant; a synonymous variant p.P51 (rs59621536) in exon 1 found in three individuals. Further in silico evaluation confirmed highly HAND2 conservation, being the 3'UTR the most polymorphic region of the gene. Additional computational analyses classified the variant as neutral, without alteration in splicing and miRNA sites. In silico predictions pointed to alteration of two CpG islands adjacent to the variant; however, we did not observe any alterations on the methylation pattern of HAND2 gene in our sample. Moreover, alteration of the binding site of MeCP2, a nuclear protein involved in DNA methylation, was predicted along with alteration in HAND2 mRNA structure.

Conclusions: Considering HAND2 being a well conserved gene, further studies with a larger sample should be performed to evaluate the role this gene on genetic susceptibility to TE.

Keywords: HAND2; Teratogenesis; polymorphism; thalidomide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple* / chemically induced
  • Abnormalities, Multiple* / genetics
  • Basic Helix-Loop-Helix Transcription Factors* / genetics
  • Female
  • Fetal Diseases* / chemically induced
  • Fetal Diseases* / genetics
  • Genetic Predisposition to Disease
  • Heart Defects, Congenital* / chemically induced
  • Heart Defects, Congenital* / genetics
  • Humans
  • Pregnancy
  • Thalidomide* / toxicity


  • Thalidomide
  • HAND2 protein, human
  • Basic Helix-Loop-Helix Transcription Factors