Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction

Genet Med. 2018 Feb;20(2):250-258. doi: 10.1038/gim.2017.105. Epub 2017 Aug 10.


PurposeFetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver-Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.MethodsWhole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.ResultsWe report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.ConclusionGenetic defects of the HMGA2-PLAG1-IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Epigenesis, Genetic
  • Facies
  • Female
  • Fetal Growth Retardation / diagnosis
  • Fetal Growth Retardation / genetics*
  • Fetal Growth Retardation / metabolism*
  • Gene Expression Regulation, Developmental
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genotype
  • Growth Charts
  • HMGA2 Protein / genetics*
  • HMGA2 Protein / metabolism
  • Humans
  • Insulin-Like Growth Factor II / genetics*
  • Insulin-Like Growth Factor II / metabolism
  • Models, Biological
  • Mutation
  • Pedigree
  • Signal Transduction
  • Silver-Russell Syndrome / diagnosis
  • Silver-Russell Syndrome / genetics
  • Silver-Russell Syndrome / metabolism
  • Whole Genome Sequencing


  • DNA-Binding Proteins
  • HMGA2 Protein
  • IGF2 protein, human
  • PLAG1 protein, human
  • Insulin-Like Growth Factor II