OTX2 duplications: a recurrent cause of oculo-auriculo-vertebral spectrum
Tristan Celse
,
Angèle Tingaud-Sequeira
(1)
,
Klaus Dieterich
(2, 3)
,
Geraldine Siegfried
(4)
,
Cédric Lecaignec
,
Laurence Bouneau
(5)
,
Madeleine Fannemel
,
Gaelle Salaun
(6)
,
Fanny Laffargue
(7)
,
Guillaume Martinez
(8)
,
Véronique Satre
(9)
,
Gaelle Vieville
(10)
,
Marie Bidart
(11)
,
Cecilia Soussi Zander
,
Ann-Charlotte Turesson
,
Miranda Splitt
(12)
,
Dorothee Reboul
(13, 14)
,
Jean Chiesa
(15, 14)
,
Philippe Khau van Kien
(16, 17, 18)
,
Manon Godin
(19)
,
Nicolas Gruchy
(20, 21)
,
Himanshu Goel
,
Elizabeth Palmer
(22)
,
Kalliope Demetriou
,
Carolyn Shalhoub
,
Caroline Rooryck
(1)
,
Charles Coutton
(23)
1
U1211 INSERM/MRGM -
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
2 GIN - [GIN] Grenoble Institut des Neurosciences
3 CRCT - Centre de Recherches en Cancérologie de Toulouse
4 Hémostase et thrombose
5 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
6 CHU Clermont-Ferrand
7 Service de Génétique Médicale [CHU Clermont-Ferrand]
8 Hôpital Couple-Enfant, Centre Hospitalier Universitaire de Grenoble, UM de Génétique Chromosomique, F-38000, Grenoble, France
9 AGIM - AGeing and IMagery
10 Laboratoire de biochimie et génétique moléculaire
11 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
12 Institute of Genetic Medicine [Newcastle]
13 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
14 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
15 CHU Nîmes - Hôpital Universitaire Carémeau [Nîmes]
16 Service de génétique [CHU HEGP]
17 LPPCE - Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaire Expérimentale
18 Service de Cardiologie [CHU de Dijon]
19 Service de Génétique [CHU Caen]
20 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
21 CHU Caen
22 USC - Department of Electrical and Computer Engineering, University of Southern California, 3737 Watt Way, Los Angeles, CA 90089-0271, USA
23 Laboratoire de Génétique Chromosomique [CHU de Grenoble]
2 GIN - [GIN] Grenoble Institut des Neurosciences
3 CRCT - Centre de Recherches en Cancérologie de Toulouse
4 Hémostase et thrombose
5 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
6 CHU Clermont-Ferrand
7 Service de Génétique Médicale [CHU Clermont-Ferrand]
8 Hôpital Couple-Enfant, Centre Hospitalier Universitaire de Grenoble, UM de Génétique Chromosomique, F-38000, Grenoble, France
9 AGIM - AGeing and IMagery
10 Laboratoire de biochimie et génétique moléculaire
11 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
12 Institute of Genetic Medicine [Newcastle]
13 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
14 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
15 CHU Nîmes - Hôpital Universitaire Carémeau [Nîmes]
16 Service de génétique [CHU HEGP]
17 LPPCE - Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaire Expérimentale
18 Service de Cardiologie [CHU de Dijon]
19 Service de Génétique [CHU Caen]
20 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
21 CHU Caen
22 USC - Department of Electrical and Computer Engineering, University of Southern California, 3737 Watt Way, Los Angeles, CA 90089-0271, USA
23 Laboratoire de Génétique Chromosomique [CHU de Grenoble]
Tristan Celse
- Fonction : Auteur
Angèle Tingaud-Sequeira
- Fonction : Auteur
- PersonId : 1229022
- ORCID : 0000-0003-1103-2158
Cédric Lecaignec
- Fonction : Auteur
Madeleine Fannemel
- Fonction : Auteur
Cecilia Soussi Zander
- Fonction : Auteur
Ann-Charlotte Turesson
- Fonction : Auteur
Himanshu Goel
- Fonction : Auteur
Kalliope Demetriou
- Fonction : Auteur
Carolyn Shalhoub
- Fonction : Auteur
Caroline Rooryck
- Fonction : Auteur
- PersonId : 1229023
- ORCID : 0000-0002-9789-3591
Charles Coutton
- Fonction : Auteur
- PersonId : 764155
- ORCID : 0000-0002-8873-8098
- IdRef : 137277547
Résumé
Background Oculo-auriculo-vertebral spectrum (OAVS) is the second most common cause of head and neck malformations in children after orofacial clefts. OAVS is clinically heterogeneous and characterised by a broad range of clinical features including ear anomalies with or without hearing loss, hemifacial microsomia, orofacial clefts, ocular defects and vertebral abnormalities. Various genetic causes were associated with OAVS and copy number variations represent a recurrent cause of OAVS, but the responsible gene often remains elusive. Methods We described an international cohort of 17 patients, including 10 probands and 7 affected relatives, presenting with OAVS and carrying a 14q22.3 microduplication detected using chromosomal microarray analysis. For each patient, clinical data were collected using a detailed questionnaire addressed to the referring clinicians. We subsequently studied the effects of OTX2 overexpression in a zebrafish model. Results We defined a 272 kb minimal common region that only overlaps with the OTX2 gene. Head and face defects with a predominance of ear malformations were present in 100% of patients. The variability in expressivity was significant, ranging from simple chondromas to severe microtia, even between intrafamilial cases. Heterologous overexpression of OTX2 in zebrafish embryos showed significant effects on early development with alterations in craniofacial development. Conclusions Our results indicate that proper OTX2 dosage seems to be critical for the normal development of the first and second branchial arches. Overall, we demonstrated that OTX2 genomic duplications are a recurrent cause of OAVS marked by auricular malformations of variable severity.