title: Agnathia-otocephaly complex and asymmetric velopharyngeal insufficiency due to an in-frame duplication in OTX2.
abstract: Agnathia-otocephaly complex is a malformation characterized by absent/hypoplastic mandible and abnormally positioned ears. Mutations in two genes, PRRX1 and OTX2, have been described in a small number of families with this disorder. We performed clinical and genetic testing in an additional family. The proband is a healthy female with a complicated pregnancy history that includes two offspring diagnosed with agnathia-otocephaly during prenatal ultrasound scans. Exome sequencing was performed in fetal DNA from one of these two offspring revealing a heterozygous duplication in OTX2: c.271_273dupCAG, p.(Gln91dup). This change leads to the insertion of a glutamine within the OTX2 homeodomain region, and is predicted to alter this signaling molecule's ability to interact with DNA. The same variant was also identified in the proband's clinically unaffected 38-year-old husband and their 9-year-old daughter, who presented with a small mandible, normal ears and velopharyngeal insufficiency due to a short hemi-palate. This unusual presentation of OTX2-related disease suggests that OTX2 might have a role in palatal hypoplasia cases. A previously unreported OTX2 variant associated with extreme intrafamilial variability is described and the utility of exome sequencing as a tool to confirm the diagnosis of agnathia-otocephaly and to inform the reproductive decisions of affected families is highlighted.
authors.affiliation: 1] Institute of Human Development, University of Manchester, Manchester, UK [2] Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Panagiotis I
authors.initials: PI
authors.lastname: Sergouniotis
authors.affiliation: 1] Institute of Human Development, University of Manchester, Manchester, UK [2] Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Williams
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Sanjeev S
authors.initials: SS
authors.lastname: Bhaskar
authors.affiliation: 1] Institute of Human Development, University of Manchester, Manchester, UK [2] Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
authors.affiliation: Department of Computational and Evolutionary Biology, Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Lovell
authors.affiliation: North West, Isle of Man and North Wales Cleft Lip and Palate Network, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Whitby
authors.affiliation: 1] Institute of Human Development, University of Manchester, Manchester, UK [2] Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: 1] Institute of Human Development, University of Manchester, Manchester, UK [2] Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000328:Adult; D002648:Child; D005260:Female; D020440:Gene Duplication; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D051857:Otx Transcription Factors / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D016364:Reading Frames; D014681:Velopharyngeal Insufficiency / Q000175:diagnosis / Q000235:genetics*
chemical_list: C497659:OTX2 protein, human; D051857:Otx Transcription Factors