title: OTX2 duplication is implicated in hemifacial microsomia.
abstract: 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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Dina
authors.initials: D
authors.lastname: Zielinski
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Barak
authors.initials: B
authors.lastname: Markus
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Mona
authors.initials: M
authors.lastname: Sheikh
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America; Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gymrek
authors.affiliation: Counsyl, South San Francisco, California, United States of America.
authors.forename: Clement
authors.initials: C
authors.lastname: Chu
authors.affiliation: Rambam Health Care Campus, Haifa, Israel.
authors.forename: Marta
authors.initials: M
authors.lastname: Zaks
authors.affiliation: Counsyl, South San Francisco, California, United States of America.
authors.forename: Balaji
authors.initials: B
authors.lastname: Srinivasan
authors.affiliation: Division of Genetics, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Jodi D
authors.initials: JD
authors.lastname: Hoffman
authors.affiliation: Rambam Health Care Campus, Haifa, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Aizenbud
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Erlich
mesh_terms: D000818:Animals; D058674:Chromosome Duplication; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D006053:Goldenhar Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D051857:Otx Transcription Factors / Q000235:genetics*
chemical_list: C497659:OTX2 protein, human; D051857:Otx Transcription Factors