Universität zu Köln

Pauli, Silke, Altmueller, Janine, Schroeder, Simone, Ohlenbusch, Andreas, Dreha-Kulaczewski, Steffi, Bergmann, Carsten, Nuernberg, Peter, Thiele, Holger, Li, Yun, Wollnik, Bernd and Brockmann, Knut (2019). Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome. J. Med. Genet., 56 (4). S. 261 - 265. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

Full text not available from this repository.

Abstract

Background Joubert syndrome (JBTS) is a rare neurodevelopmental disorder with marked phenotypic variability and genetic heterogeneity. Homozygous or compound heterozygous mutations in the KIAA0586 gene on chromosome 14q23 are known to be associated with JBTS-23. The frameshift variant c.428delG is the most frequent KIAA0586 variant reported in JBTS-23; yet, homozygosity of this variant was observed in two patients with JBTS-23. However, homozygosity of the c.428delG variant was recently reported as well in one healthy individual. Objective To clarify whether the frameshift variant c.428delG in KIAA0586 is pathogenic in the homozygous state. Methods Whole-exome sequencing as well as RNA analysis were performed. Results We identified biallelic mutations, including the variant c.428delG and a splice site variant c.1413-1G>C, in KIAA0586 in two siblings with clinical and MRI features of JBTS. The c.1413-1G>C variant was inherited from the healthy father. The c.428delG variant was found in the healthy mother in a homozygous state in blood lymphocytes, hair root cells and buccal epithelial cells. RNA analysis revealed that the transcript harbouring the c.428delG variant was expressed in blood cells from the healthy mother, indicating that transcripts harbouring this variant elude the mechanism of nonsense-mediated mRNA decay. Conclusion Considering this and the high allele frequency of 0.003117 in the gnomAD database, we conclude that c.428delG represents a JBTS disease-causing variant only if present in compound heterozygous state with a more severe KIAA0586 variant, but not in a homozygous situation.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pauli, Silke UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Simone UNSPECIFIED UNSPECIFIED UNSPECIFIED Ohlenbusch, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Dreha-Kulaczewski, Steffi UNSPECIFIED UNSPECIFIED UNSPECIFIED Bergmann, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Yun UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Brockmann, Knut UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-151517
DOI:	10.1136/jmedgenet-2018-105470
Journal or Publication Title:	J. Med. Genet.
Volume:	56
Number:	4
Page Range:	S. 261 - 265
Date:	2019
Publisher:	BMJ PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1468-6244
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TALPID3 GENE; DISORDERS; MUTATIONS Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15151