Universität zu Köln

Kause, Franziska, Reutter, Heiko, Marsch, Florian, Thiele, Holger, Altmueller, Janine, Ludwig, Michael and Zhang, Rong (2018). Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchio-otic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance? Mol. Med. Rep., 17 (2). S. 3200 - 3206. ATHENS: SPANDIDOS PUBL LTD. ISSN 1791-3004

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Abstract

Branchio-otic (BO) syndrome is a clinically and genetically heterogeneous disorder that presents with variable branchial arch and otic anomalies. Dominant mutations in the human homologues of the Drosophila eyes absent (EYA1) gene, and the Drosophila sine oculis homeobox 1 and 5 (SIX1 and SIX5, respectively) genes have been causally associated with BO syndrome. Esophageal atresia (EA), with or without tracheo-esophageal fistula (TEF), is the most common type of malformation of the upper digestive tract. To date, its causes are poorly understood. The present study investigated a family with three affected members who all presented with classic BO associated symptoms. Notably, the index patient also presented with the most common EA/TEF subtype type 3b. Whole exome sequencing (WES) was performed in the index patient, and prioritized genetic variants and their segregation in the family were analyzed by Sanger sequencing. WES demonstrated a known disease-causing heterozygous EYA1 splice variant in the patient, as well as his sister and mother; all of whom were affected with BO syndrome. A further GLI family zinc finger 3 (GLI3) splice variant of unknown significance, inherited from the unaffected father, was also detected in the index patient. EYA1 and GLI3 are involved in the Sonic Hedgehog transcriptional network and GLI3 seems to be involved in human foregut malformations. Therefore, one may hypothesize a digenic inheritance model involving EYA1 and GLI3, where the effect of the GLI3 variant observed here only emerges in the background of the EYA1 defect.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kause, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Reutter, Heiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Marsch, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Ludwig, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Rong UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-198160
DOI:	10.3892/mmr.2017.8196
Journal or Publication Title:	Mol. Med. Rep.
Volume:	17
Number:	2
Page Range:	S. 3200 - 3206
Date:	2018
Publisher:	SPANDIDOS PUBL LTD
Place of Publication:	ATHENS
ISSN:	1791-3004
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRACHEOESOPHAGEAL FISTULA; BOR SYNDROME; GENE; PROGENITORS; SPECTRUM; DEFECTS; TRACT; FGF10; LUNG; SHH Multiple languages Oncology; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19816