OTX2 duplications: a recurrent cause of oculo-auriculo-vertebral spectrum
Tristan Celse
(1, 2)
,
Angèle Tingaud-Sequeira
(3)
,
Klaus Dieterich
(4, 5)
,
Geraldine Siegfried
(6)
,
Cédric Lecaignec
(7, 8)
,
Laurence Bouneau
(7)
,
Madeleine Fannemel
(9)
,
Gaelle Salaun
(10, 11)
,
Fanny Laffargue
(12)
,
Guillaume Martinez
(1, 2)
,
Véronique Satre
(1, 2)
,
Gaelle Vieville
(13)
,
Marie Bidart
(14, 2, 13)
,
Cecilia Soussi Zander
(15)
,
Ann-Charlotte Turesson
(15)
,
Miranda Splitt
(16)
,
Dorothee Reboul
(17, 18)
,
Jean Chiesa
(19, 18)
,
Philippe Khau van Kien
(19, 18)
,
Manon Godin
(20, 21)
,
Nicolas Gruchy
(22, 23)
,
Himanshu Goel
(24, 25)
,
Elizabeth Palmer
(26, 27)
,
Kalliope Demetriou
(26)
,
Carolyn Shalhoub
(26, 27)
,
Caroline Rooryck
(3)
,
Charles Coutton
(28, 1)
1
UGA -
Université Grenoble Alpes
2 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
3 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
4 GIN - [GIN] Grenoble Institut des Neurosciences
5 CRCT - Centre de Recherches en Cancérologie de Toulouse
6 Inserm U1312 - BRIC - BoRdeaux Institute in onCology
7 Institut Fédératif de Biologie (IFB)
8 ToNIC - Toulouse NeuroImaging Center
9 Oslo University Hospital [Oslo]
10 CHU Clermont-Ferrand
11 IMoST - Imagerie Moléculaire et Stratégies Théranostiques
12 Service Génétique Médicale [CHU Clermont-Ferrand]
13 Laboratoire de biochimie et génétique moléculaire
14 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
15 Uppsala University Hospital
16 Institute of Genetic Medicine [Newcastle]
17 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
18 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
19 CHU Nîmes - Hôpital Universitaire Carémeau [Nîmes]
20 Service de Génétique [CHU Caen]
21 UNICAEN - Université de Caen Normandie
22 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
23 CHU Caen
24 Hunter Genetics
25 UoN - University of Newcastle [Callaghan, Australia]
26 Sydney Children's hospital
27 UNSW Faculty of Medicine [Sydney]
28 Laboratoire de Génétique Chromosomique [CHU de Grenoble]
2 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
3 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
4 GIN - [GIN] Grenoble Institut des Neurosciences
5 CRCT - Centre de Recherches en Cancérologie de Toulouse
6 Inserm U1312 - BRIC - BoRdeaux Institute in onCology
7 Institut Fédératif de Biologie (IFB)
8 ToNIC - Toulouse NeuroImaging Center
9 Oslo University Hospital [Oslo]
10 CHU Clermont-Ferrand
11 IMoST - Imagerie Moléculaire et Stratégies Théranostiques
12 Service Génétique Médicale [CHU Clermont-Ferrand]
13 Laboratoire de biochimie et génétique moléculaire
14 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
15 Uppsala University Hospital
16 Institute of Genetic Medicine [Newcastle]
17 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
18 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
19 CHU Nîmes - Hôpital Universitaire Carémeau [Nîmes]
20 Service de Génétique [CHU Caen]
21 UNICAEN - Université de Caen Normandie
22 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
23 CHU Caen
24 Hunter Genetics
25 UoN - University of Newcastle [Callaghan, Australia]
26 Sydney Children's hospital
27 UNSW Faculty of Medicine [Sydney]
28 Laboratoire de Génétique Chromosomique [CHU de Grenoble]
Angèle Tingaud-Sequeira
- Fonction : Auteur
- PersonId : 1229022
- ORCID : 0000-0003-1103-2158
Cédric Lecaignec
- Fonction : Auteur
Dorothee Reboul
- Fonction : Auteur
- PersonId : 1394802
Jean Chiesa
- Fonction : Auteur
- PersonId : 1390698
- ORCID : 0000-0002-7001-0816
Philippe Khau van Kien
- Fonction : Auteur
- PersonId : 1179369
- IdHAL : philippe-khau-van-kien
- ORCID : 0000-0001-7754-969X
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.