title: Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients.
abstract: BACKGROUND
  Oculo-auriculo-vertebral spectrum (OAVS OMIM 164210) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood.
  
  
  METHODS
  We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci.
  
  
  RESULTS
  Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened.
  
  
  CONCLUSIONS
  In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations. We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis. Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s).
authors.affiliation: Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. Electronic address: ana.beleza@me.com.
authors.forename: Ana
authors.initials: A
authors.lastname: Beleza-Meireles
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Mersey Regional Genetic Service, Alder Hey Hospital, Liverpool, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hart
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Central Manchester University Hospitals NHS Foundation Trust as part of Manchester Academic Health Science Centre (MAHSC), Manchester, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Renata
authors.initials: R
authors.lastname: Oliveira
authors.affiliation: Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Cláudia Falcão
authors.initials: CF
authors.lastname: Reis
authors.affiliation: Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Venâncio
authors.affiliation: Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Ramos
authors.affiliation: Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Sá
authors.affiliation: Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Lina
authors.initials: L
authors.lastname: Ramos
authors.affiliation: Unidade Hematologia Molecular, Serviço de Hematologia, CHUC, Portugal.
authors.forename: Elizabete
authors.initials: E
authors.lastname: Cunha
authors.affiliation: Faculdade de Medicina da Universidade de Coimbra, Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Luís Miguel
authors.initials: LM
authors.lastname: Pires
authors.affiliation: Faculdade de Medicina da Universidade de Coimbra, Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Isabel Marques
authors.initials: IM
authors.lastname: Carreira
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Scholey
authors.affiliation: Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, USA.
authors.forename: Ronnie
authors.initials: R
authors.lastname: Wright
authors.affiliation: Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, USA.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Briggs
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Kingston
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Kay
authors.initials: K
authors.lastname: Metcalfe
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Central Manchester University Hospitals NHS Foundation Trust as part of Manchester Academic Health Science Centre (MAHSC), Manchester, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculdade de Medicina da Universidade de Coimbra, Laboratório de Citogenética e Genómica - Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Jorge Manuel
authors.initials: JM
authors.lastname: Saraiva
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Central Manchester University Hospitals NHS Foundation Trust as part of Manchester Academic Health Science Centre (MAHSC), Manchester, UK. Electronic address: m.tassabehji@manchester.ac.uk.
authors.forename: May
authors.initials: M
authors.lastname: Tassabehji
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D001921:Brain / Q000002:abnormalities; D055028:Comparative Genomic Hybridization; D002658:Developmental Disabilities / Q000235:genetics*; D004423:Ear / Q000002:abnormalities / Q000196:embryology; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics; D005260:Female; D006053:Goldenhar Syndrome / Q000175:diagnosis / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics; D006548:Hernia, Diaphragmatic / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D008297:Male; D013131:Spine / Q000002:abnormalities
keywords: Copy number variation; First and second branchial arch; Goldenhar syndrome; Hemifacial microsomia; Oculoauriculovertebral spectrum; Preauricular tags