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Homozygosity Mapping and Whole Exome Sequencing Reveal a Novel Homozygous COL18A1 Mutation Causing Knobloch Syndrome
- Source :
- PLOS ONE, PLoS ONE, PLoS ONE, 9 (11), PLoS ONE, Vol 9, Iss 11, p e112747 (2014)
- Publication Year :
- 2014
- Publisher :
- Public Library of Science (PLoS), 2014.
-
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. ISSN:1932-6203
- Subjects :
- Male
Proband
Heredity
Genetic Linkage
Molecular biology
lcsh:Medicine
Iran
Blindness
Bioinformatics
Collagen Type XIII
Homozygosity
11124 Institute of Medical Molecular Genetics
Consanguinity
Sequencing techniques
Medicine and Health Sciences
Myopia
Knobloch syndrome
Protein Isoforms
Exome
Autosomal Linkage
DNA sequencing
lcsh:Science
Child
Frameshift Mutation
Exome sequencing
Encephalocele
Visual Impairments
Genetics
Sanger sequencing
Multidisciplinary
Homozygote
Retinal Degeneration
Retinal dystrophy
Chromosome Mapping
Genomics
Disease gene identification
Pedigree
3. Good health
Codon, Nonsense
symbols
Retinal Disorders
Female
Transcriptome Analysis
Linkage analysis
Research Article
SNP array
Next-Generation Sequencing
Heterozygote
Molecular Sequence Data
610 Medicine & health
1100 General Agricultural and Biological Sciences
Biology
Human Genomics
Chromosomal Inheritance
Frameshift mutation
Molecular Genetics
symbols.namesake
1300 General Biochemistry, Genetics and Molecular Biology
medicine
Humans
Inherited Eye Disorders
1000 Multidisciplinary
Base Sequence
Biology and life sciences
Genome, Human
lcsh:R
High Throughput Sequencing
Whole exome sequencing
Retinal Detachment
Dideoxy DNA sequencing
Computational Biology
Sequence Analysis, DNA
Genome Analysis
medicine.disease
Ophthalmology
Molecular biology techniques
Mutation
570 Life sciences
biology
lcsh:Q
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....de72236abe78cd2e3544d7c92f46679a