OTX2 duplication is implicated in hemifacial microsomia

PLoS One. 2014 May 9;9(5):e96788. doi: 10.1371/journal.pone.0096788. eCollection 2014.


Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. We investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. Whole-exome sequencing results indicated the absence of a pathogenic coding point mutation. A genome-wide survey of segmental variations identified a 1.3 Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is consistent with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of the study. Our findings suggest a role for OTX2 dosage sensitivity in human craniofacial development and raise the possibility of a shared etiology between a subtype of hemifacial microsomia and medulloblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosome Duplication
  • Chromosomes, Human, Pair 14 / genetics
  • DNA Copy Number Variations / genetics
  • Exons / genetics
  • Female
  • Gene Duplication*
  • Goldenhar Syndrome / genetics*
  • Humans
  • Male
  • Mice
  • Otx Transcription Factors / genetics*


  • OTX2 protein, human
  • Otx Transcription Factors

Grants and funding

The study was funded by Whitehead Institute internal funds and private donations from Andria and Paul Heafy, Cathy and Jim Stone, and Ron Casty. Two authors, Drs. Balaji Srinivasan and Clement Chu, are from Counsyl Inc, a for-profit company. Their role in the manuscript was generation of the sequencing data. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.