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Article Dans Une Revue Journal of Medical Genetics Année : 2022

OTX2 duplications: a recurrent cause of oculo-auriculo-vertebral spectrum

Tristan Celse
  • Fonction : Auteur
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

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.
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Dates et versions

hal-03996847 , version 1 (20-02-2023)

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Citer

Tristan Celse, Angèle Tingaud-Sequeira, Klaus Dieterich, Geraldine Siegfried, Cédric Lecaignec, et al.. OTX2 duplications: a recurrent cause of oculo-auriculo-vertebral spectrum. Journal of Medical Genetics, 2022, pp.jmedgenet-2022-108678. ⟨10.1136/jmg-2022-108678⟩. ⟨hal-03996847⟩
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