title: EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state.
abstract: Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%-6% of WS2.
authors.affiliation: INSERM U955, IMRB, Equipe 6, Créteil, France.|Université Paris 12, Faculté de Médecine, Créteil, France.|INSERM U1163, Institut IMAGINE, Equipe Embryologie et Génétique des Malformations Humaines, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Issa
authors.affiliation: INSERM U955, IMRB, Equipe 6, Créteil, France.|Université Paris 12, Faculté de Médecine, Créteil, France.|INSERM U1163, Institut IMAGINE, Equipe Embryologie et Génétique des Malformations Humaines, Paris, France.
authors.forename: Nadege
authors.initials: N
authors.lastname: Bondurand
authors.affiliation: AP-HP, Groupe Henri Mondor-Albert Chenevier, Département de Génétique, Créteil, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Faubert
authors.affiliation: AP-HP, Hôpital Necker, Laboratoire de Génétique Moléculaire, Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Poisson
authors.affiliation: INSERM U955, IMRB, Equipe 6, Créteil, France.|Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Lecerf
authors.affiliation: INSERM U1163, Institut IMAGINE, Bioinformatique, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: ENT Department and Audio-Phonological Center, Cliniques universitaires St Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Naima
authors.initials: N
authors.lastname: Deggouj
authors.affiliation: AP-HP, Service d'ORL, Hôpital Necker, Paris, France.
authors.forename: Natalie
authors.initials: N
authors.lastname: Loundon
authors.affiliation: AP-HP, Hôpital Necker, Laboratoire de Génétique Moléculaire, Paris, France.|AP-HP, Centre de référence «Surdités génétiques», Hôpital Necker, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Jonard
authors.affiliation: Centre hospitalier universitaire de Nantes, Service de Génétique Médicale, Nantes, France.
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.affiliation: Centre de génétique humaine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Sznajer
authors.affiliation: Centre Hospitalier Universitaire de Montpellier, Département de Génétique Médicale, Montpellier, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Blanchet
authors.affiliation: INSERM U1163, Institut IMAGINE, Equipe Embryologie et Génétique des Malformations Humaines, Paris, France.|AP-HP, Centre de référence «Surdités génétiques», Hôpital Necker, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.affiliation: INSERM U955, IMRB, Equipe 6, Créteil, France.|INSERM U1163, Institut IMAGINE, Equipe Embryologie et Génétique des Malformations Humaines, Paris, France.|AP-HP, Groupe Henri Mondor-Albert Chenevier, Département de Génétique, Créteil, France.|AP-HP, Hôpital Necker, Laboratoire de Génétique Moléculaire, Paris, France.|Université Paris-Descartes, Faculté de Médecine, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Pingault
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007498:Iris; D008297:Male; D009154:Mutation; D059645:Mutation Rate; D010375:Pedigree; D010641:Phenotype; D021381:Protein Transport; D022821:RNA Splice Sites; D044023:Receptor, Endothelin B / Q000235:genetics* / Q000378:metabolism; D014849:Waardenburg Syndrome / Q000175:diagnosis* / Q000235:genetics*; D055815:Young Adult
chemical_list: C000588596:EDNRB protein, human; D022821:RNA Splice Sites; D044023:Receptor, Endothelin B
keywords: G protein-coupled receptor; Waardenburg syndrome; endothelin; neurocristopathy