Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy

Autor: Christian Gilissen, F. Nienke Boonstra, Joris A. Veltman, Ellen A.W. Blokland, Nienke Wieskamp, Carmen Ayuso, Frans P.M. Cremers, Konstantinos Nikopoulos, Rob W.J. Collin, C. Erik van Nouhuys, Hans Scheffer, Peer Arts, Arijit Mukhopadhyay, Tim M. Strom, Lies H. Hoefsloot, Sanne Bouwhuis, Mauk A. D. Tilanus, Alexander Hoischen
Přispěvatelé: Nikopoulos, Konstantinos, Gilissen, Christian, Hoischen, Alexander, Erik van Nouhuys, C, Boonstra, F Nienke, Blokland, Ellen AW, Arts, Peer, Wieskamp, Nienke, Strom, Tim M, Ayuso, Carmen, Tilanus, Mauk AD, Bouwhuis, Sanne, Mukhopadhyay, Arijit, Scheffer, Hans, Hoefsloot, Lies H, Veltman, Joris A, Cremers, Frans PM, Collin, Rob WJ
Rok vydání: 2009
Předmět:
Male
FZD4
Genetics and epigenetic pathways of disease [NCMLS 6]
Sequence analysis
Fundus Oculi
Genetic Linkage
Tetraspanins
DNA Mutational Analysis
Molecular Sequence Data
Mutation
Missense
Genome-wide association study
Locus (genetics)
Biology
Polymorphism
Single Nucleotide
Genomic disorders and inherited multi-system disorders [IGMD 3]
TSPAN12
Retinal Diseases
Genetic linkage
Report
medicine
Genetics
Humans
Genetics(clinical)
Family
Amino Acid Sequence
Base Pairing
Genetics (clinical)
Base Sequence
Haplotype
familial exudative vitreoretinopathy
Membrane Proteins
Sequence Analysis
DNA
medicine.disease
Pedigree
Evaluation of complex medical interventions [NCEBP 2]
Mutation
Familial exudative vitreoretinopathy
Female
mutation
Functional Neurogenomics [DCN 2]
SNP array
Genome-Wide Association Study
Zdroj: American Journal of Human Genetics, 86, 240-7
American Journal of Human Genetics, 86, 2, pp. 240-7
ISSN: 1537-6605
0002-9297
Popis: Contains fulltext : 89704.pdf (Publisher’s version ) (Closed access) Familial exudative vitreoretinopathy (FEVR) is a genetically heterogeneous retinal disorder characterized by abnormal vascularisation of the peripheral retina, often accompanied by retinal detachment. To date, mutations in three genes (FZD4, LRP5, and NDP) have been shown to be causative for FEVR. In two large Dutch pedigrees segregating autosomal-dominant FEVR, genome-wide SNP analysis identified an FEVR locus of approximately 40 Mb on chromosome 7. Microsatellite marker analysis suggested similar at risk haplotypes in patients of both families. To identify the causative gene, we applied next-generation sequencing in the proband of one of the families, by analyzing all exons and intron-exon boundaries of 338 genes, in addition to microRNAs, noncoding RNAs, and other highly conserved genomic regions in the 40 Mb linkage interval. After detailed bioinformatic analysis of the sequence data, prioritization of all detected sequence variants led to three candidates to be considered as the causative genetic defect in this family. One of these variants was an alanine-to-proline substitution in the transmembrane 4 superfamily member 12 protein, encoded by TSPAN12. This protein has very recently been implicated in regulating the development of retinal vasculature, together with the proteins encoded by FZD4, LRP5, and NDP. Sequence analysis of TSPAN12 revealed two mutations segregating in five of 11 FEVR families, indicating that mutations in TSPAN12 are a relatively frequent cause of FEVR. Furthermore, we demonstrate the power of targeted next-generation sequencing technology to identify disease genes in linkage intervals.
Databáze: OpenAIRE
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