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Hum Mutat. 2017 May;38(5):581-593. doi: 10.1002/humu.23206. Epub 2017 Mar 15.

EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state.

Author information

1
INSERM U955, IMRB, Equipe 6, Créteil, France.
2
Université Paris 12, Faculté de Médecine, Créteil, France.
3
INSERM U1163, Institut IMAGINE, Equipe Embryologie et Génétique des Malformations Humaines, Paris, France.
4
AP-HP, Groupe Henri Mondor-Albert Chenevier, Département de Génétique, Créteil, France.
5
AP-HP, Hôpital Necker, Laboratoire de Génétique Moléculaire, Paris, France.
6
INSERM U1163, Institut IMAGINE, Bioinformatique, Paris, France.
7
ENT Department and Audio-Phonological Center, Cliniques universitaires St Luc, Université catholique de Louvain, Brussels, Belgium.
8
AP-HP, Service d'ORL, Hôpital Necker, Paris, France.
9
AP-HP, Centre de référence «Surdités génétiques», Hôpital Necker, Paris, France.
10
Centre hospitalier universitaire de Nantes, Service de Génétique Médicale, Nantes, France.
11
Centre de génétique humaine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
12
Centre Hospitalier Universitaire de Montpellier, Département de Génétique Médicale, Montpellier, France.
13
Université Paris-Descartes, Faculté de Médecine, Paris, France.

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.

KEYWORDS:

G protein-coupled receptor; Waardenburg syndrome; endothelin; neurocristopathy

PMID:
28236341
DOI:
10.1002/humu.23206
[Indexed for MEDLINE]

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