The Genetic Causes of Nonsyndromic Congenital Retinal Detachment: A Genetic and Phenotypic Study of Pakistani Families
| Autor: | Sorath Noorani Siddiqui, Vafa Keser, Rui Chen, Ayesha Khan, Jacek Majewski, Huanan Ren, Irma Lopez, Robert K. Koenekoop, Javad Nadaf, Raheel Qamar |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine LRP5 Genotype DNA Mutational Analysis Single-nucleotide polymorphism Biology medicine.disease_cause Polymorphism Single Nucleotide Retina 03 medical and health sciences chemistry.chemical_compound Retinal Diseases TSPAN12 NDP Basic Helix-Loop-Helix Transcription Factors Genetics medicine Humans Pakistan Child Gene Genotyping NCRNA Exome sequencing Mutation Incidence Helix-Loop-Helix Motifs Infant Retinal ATOH7 medicine.disease Pedigree 3. Good health retinal detachments Phenotype 030104 developmental biology chemistry Child Preschool FEVR Familial exudative vitreoretinopathy Female blindness |
| Zdroj: | Investigative Ophthalmology & Visual Science |
| ISSN: | 1552-5783 |
| DOI: | 10.1167/iovs.16-20281 |
| Popis: | Purpose To evaluate consanguineous pedigrees from Pakistan with a clinical diagnosis of nonsyndromic congenital retinal nonattachment (NCRNA) and identify genes responsible for the disease as currently only one NCRNA gene is known (atonal basic helix-loop-helix transcription factor 7: ATOH7). Methods We implemented a three-step genotyping platform: single nucleotide polymorphism genotyping to identify loss of heterozygosity regions in patients, Retinal Information Network panel screening for mutations in currently known retinal genes. Negative patients were then subjected to whole exome sequencing. Results We evaluated 21 consanguineous NCRNA pedigrees and identified the causal mutations in known retinal genes in 13 out of our 21 families. We found mutations in ATOH7 in three families. Surprisingly, we then found mutations in familial exudative vitreoretinopathy (FEVR) genes; low-density lipoprotein receptor-related protein 5 mutations (six families), tetraspanin 12 mutations (two families), and NDP mutations (two families). Thus, 62% of the patients were successfully genotyped in our study with seven novel and six previously reported mutations in known retinal genes. Conclusions Although the clinical diagnosis of all children was NCRNA with severe congenital fibrotic retinal detachments, the molecular diagnosis determined that the disease process was in fact a very severe form of FEVR in 10 families. Because severe congenital retinal detachment has not been previously associated with all the FEVR genes, we have thus expanded the phenotypic spectrum of FEVR, a highly variable retinal detachment phenotype that has clinical overlap with NCRNA. We identified seven novel mutations. We also established for the first time genetic overlap between the Iranian and Pakistani populations. We identified eight NCRNA families that do not harbor mutations in any known retinal genes, suggesting novel causal genes in these families. |
| Databáze: | OpenAIRE |
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