Holoprosencephaly in the genomics era

Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):165-174. doi: 10.1002/ajmg.c.31615. Epub 2018 May 17.


Holoprosencephaly (HPE) is the direct consequence of specific genetic and/or environmental insults interrupting the midline specification of the nascent forebrain. Such disturbances can lead to a broad range of phenotypic consequences for the brain and face in humans. This malformation sequence is remarkably common in utero (1 in 250 human fetuses), but 97% typically do not survive to birth. The precise molecular pathogenesis of HPE in these early human embryos remains largely unknown. Here, we outline our current understanding of the principal driving factors leading to HPE pathologies and elaborate our multifactorial integrated genomics approach. Overall, our understanding of the pathogenesis continues to become simpler, rather than more complicated. Genomic technologies now provide unprecedented insight into disease-associated variation, including the overall extent of genetic interactions (coding and noncoding) predicted to explain divergent phenotypes.

Keywords: HPE; environmental modifier; gene driver; gene modifier; multifactorial inheritance.

Publication types

  • Review

MeSH terms

  • Animals
  • Female
  • Holoprosencephaly / embryology
  • Holoprosencephaly / genetics*
  • Humans
  • Infant, Newborn
  • Mutation*
  • Phenotype
  • Pregnancy

Supplementary concepts

  • cyclopia sequence