Universität zu Köln

Haghighi, Alireza, Tiwari, Amit, Piri, Niloofar, Nuernberg, Gudrun, Saleh-Gohari, Nasrollah, Haghighi, Amirreza, Neidhardt, John, Nuernberg, Peter and Berger, Wolfgang (2014). Homozygosity Mapping and Whole Exome Sequencing Reveal a Novel Homozygous COL18A1 Mutation Causing Knobloch Syndrome. PLoS One, 9 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

The aim of this study was to identify the genetic basis of a chorioretinal dystrophy with high myopia of unknown origin in a child of a consanguineous marriage. The proband and ten family members of Iranian ancestry participated in this study. Linkage analysis was carried out with DNA samples of the proband and her parents by using the Human SNP Array 6.0. Whole exome sequencing (WES) was performed with the patients' DNA. Specific sequence alterations within the homozygous regions identified by whole exome sequencing were verified by Sanger sequencing. Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient. Both parents were heterozygous for this sequence variation. Mutations in COL18A1 are known to cause Knobloch syndrome (KS). Retrospective analysis of clinical records of the patient revealed surgical removal of a meningocele present at birth. The clinical features shown by our patient were typical of KS with the exception of chorioretinal degeneration which is a rare manifestation. This is the first case of KS reported in a family of Iranian ancestry. We identified a novel disease-causing (deletion) mutation in the COL18A1 gene leading to a frameshift and premature stop codon in the last exon. The mutation was not present in SNP databases and was also not found in 192 control individuals. Its localization within the endostatin domain implicates a functional relevance of endostatin in KS. A combined approach of linkage analysis and WES led to a rapid identification of the disease-causing mutation even though the clinical description was not completely clear at the beginning.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Haghighi, Alireza UNSPECIFIED UNSPECIFIED UNSPECIFIED Tiwari, Amit UNSPECIFIED UNSPECIFIED UNSPECIFIED Piri, Niloofar UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Saleh-Gohari, Nasrollah UNSPECIFIED UNSPECIFIED UNSPECIFIED Haghighi, Amirreza UNSPECIFIED UNSPECIFIED UNSPECIFIED Neidhardt, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Berger, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-423347
DOI:	10.1371/journal.pone.0112747
Journal or Publication Title:	PLoS One
Volume:	9
Number:	11
Date:	2014
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COLLAGEN-XVIII; GENETIC-HETEROGENEITY; ENDOGENOUS INHIBITOR; LOCUS HETEROGENEITY; MOLECULAR ANALYSIS; ANGIOGENESIS; ENDOSTATIN; DEGENERATION; VARIANT; FORMS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42334