BOC is a modifier gene in holoprosencephaly

Mingi Hong, Kshitij Srivastava, Sungjin Kim, Benjamin L. Allen, Daniel J. Leahy, Ping Hu, Erich Roessler, Robert S. Krauss, Maximilian Muenke

Research output: Contribution to journalArticlepeer-review


Holoprosencephaly (HPE), a common developmental defect of the forebrain and midface, has a complex etiology. Heterozygous, loss-of-function mutations in the sonic hedgehog (SHH) pathway are associated with HPE. However, mutation carriers display highly variable clinical presentation, leading to an “autosomal dominant with modifier” model, in which the penetrance and expressivity of a predisposing mutation is graded by genetic or environmental modifiers. Such modifiers have not been identified. Boc encodes a SHH coreceptor and is a silent HPE modifier gene in mice. Here, we report the identification of missense BOC variants in HPE patients. Consistent with these alleles functioning as HPE modifiers, individual variant BOC proteins had either loss- or gain-of-function properties in cell-based SHH signaling assays. Therefore, in addition to heterozygous loss-of-function mutations in specific SHH pathway genes and an ill-defined environmental component, our findings identify a third variable in HPE: low-frequency modifier genes, BOC being the first identified.

Original languageEnglish (US)
Pages (from-to)1464-1470
Number of pages7
JournalHuman mutation
Issue number11
StatePublished - Nov 2017


  • BOC
  • birth defect
  • gene variant
  • holoprosencephaly
  • modifier gene
  • sonic hedgehog

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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