Homozygosity Mapping and Whole Exome Sequencing Reveal a Novel Homozygous COL18A1 Mutation Causing Knobloch Syndrome

• DOI: 10.1371/journal.pone.0112747
• Publication Date: 2014-11-13T19:32:21Z
• Authors: Alireza Haghighi; Amit Tiwari; Niloofar Piri; Gudrun Nürnberg; Nasrollah Saleh-G...; Amirreza Haghighi; John Neidhardt; Peter Nürnberg; Wolfgang Berger
• Keywords: Male; Heredity; Genetic Linkage; Molecular biology; Iran; Blindness; 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; Child; Frameshift Mutation; Encephalocele; Visual Impairments; 0303 health sciences; Q; Homozygote; Retinal Degeneration; Retinal dystrophy; R; Chromosome Mapping; Genomics; Pedigree; 3. Good health; Codon, Nonsense; Retinal Disorders; Medicine; Female; Transcriptome Analysis; Linkage analysis; Research Article; Next-Generation Sequencing; Heterozygote; Science; Molecular Sequence Data; 610; 610 Medicine & health; 1100 General Agricultural and Biological Sciences; Human Genomics; Chromosomal Inheritance; Molecular Genetics; 03 medical and health sciences; 1300 General Biochemistry, Genetics and Molecular Biology; Genetics; Humans; Inherited Eye Disorders; 1000 Multidisciplinary; Biology and life sciences; Base Sequence; Genome, Human; High Throughput Sequencing; Dideoxy DNA sequencing; Whole exome sequencing; Computational Biology; Genome Analysis; Ophthalmology; Molecular biology techniques; Mutation; 570 Life sciences; biology

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.<br/>PLoS ONE, 9 (11)<br/>ISSN:1932-6203<br/>