The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance

Daphne Lehalle (1, 2, 3) , Umut Altunoglu (4) , Ange-Line Bruel (2, 3) , Mirna Assoum (2, 3) , Yannis Duffourd (2, 3) , Alice Masurel (1) , Geneviève Baujat (5) , Bettina Bessieres (6) , Guillaume Captier (7) , Patrick Edery (8) , Nursel Elçioğlu , David Geneviève (9) , Alice Goldenberg (10) , Delphine Heron (11, 12) , Sarah Grotto (10) , Sandrine Marlin (13) , Audrey Putoux (8) , Massimiliano Rossi (8) , Pascale Saugier-Veber (14) , Stéphane Triau (15, 16) , Christelle Cabrol (17) , Myriam Vezain (14) , Catherine Vincent-Delorme (18) , Christel Thauvin-Robinet (1, 2, 3) , Julien Thevenon (1, 2, 3) , Pierre Vabres (2, 3, 19) , Patrick Callier (2, 3) , Hulya Kayserili (20) , Laurence Faivre (1, 2, 3)

1 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
2 Equipe GAD (LNC - U1231)
3 UBFC - Université Bourgogne Franche-Comté [COMUE]
4 Departement of Genetics [University of Istanbul]
5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 Laboratoire Histologie Embryologie Cytogénétique [CHU Necker]
7 Département Chirurgie Pédiatrique [CHRU Montpellier]
8 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
9 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
10 Service de génétique [Rouen]
11 CHU Pitié-Salpêtrière [AP-HP]
12 ICM - Institut du Cerveau = Paris Brain Institute
13 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
14 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
15 Service de foetopathologie (CHU d'Angers)
16 CHU Angers - Centre Hospitalier Universitaire d'Angers
17 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
18 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
19 Service de Dermatologie (CHU de Dijon)
20 Istanbul University

The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next-generation sequencing strategy performed on blood-derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.

Mots clés: Oculoauriculofrontonasal syndrome; frontonasal dysplasia; whole exome sequencing; whole genome sequencing

Domaines: Génétique humaine

Daphne Lehalle, Umut Altunoglu, Ange-Line Bruel, Mirna Assoum, Yannis Duffourd, et al.. The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance. American Journal of Medical Genetics Part A, 2018, 176 (12), pp.2740-2750. ⟨10.1002/ajmg.a.40662⟩. ⟨hal-02005698⟩