A newly recognized multiple malformation syndrome with caudal regression associated with a biallelic c.402G>A variant in TBX4

Eur J Hum Genet. 2020 May;28(5):669-673. doi: 10.1038/s41431-020-0572-5. Epub 2020 Jan 21.


The T-box4 (TBX4) gene (OMIM *601719) belongs to the T-box family of transcription regulators that share a conserved homology domain and are expressed at specific sites during various stages of embryonic development. Tbx4 has been found to be a crucial transcriptional regulator in embryonic hindlimb development in animal models. Monoallelic variants in the TBX4 gene are reported to be associated with skeletal defects of the pelvis and lower limbs. We report here a fetus with a novel multiple malformation syndrome associated with sacrococcygeal agenesis, bilateral lower limb aplasia, hypoplastic left heart, bilateral lung hypoplasia, hydroureteronephrosis, and nonimmune fetal hydrops, found to have a homozygous nonsense variant in the TBX4 gene. We propose that biallelic variants in the TBX4 gene are associated with a severe syndromic phenotype of sacrococcygeal agenesis and lower limb reduction defects.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Codon, Nonsense
  • Female
  • Fetus / abnormalities*
  • Humans
  • Lower Extremity Deformities, Congenital / genetics
  • Pelvis / abnormalities
  • Pregnancy
  • T-Box Domain Proteins / genetics*
  • Young Adult


  • Codon, Nonsense
  • T-Box Domain Proteins
  • TBX4 protein, human