Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies
| Autor: | M. Hashem, Mohammed Al-Owain, Arman Khan, A. Al‐Aqeel, Wesam Kurdi, M.A. Aldahmesh, Zuhair Rahbeeni, Hamad Al-Zaidan, Ranad Shaheen, Nisha Patel, Nicola G. Ghazi, Firdous Abdulwahab, S.S. Alzahrani, Eissa Faqeih, Niema Ibrahim, Hisham Alkuraya, Amal Al-Hemidan, M. Abouelhoda, Dorota Monies, Fowzan S. Alkuraya, Tawfeg Ben-Omran, M.Z. Seidahmed, S.R. Nowailaty |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genotype Genes Recessive Biology Polymorphism Single Nucleotide Workflow Consanguinity 03 medical and health sciences Retinal Dystrophies Exome Sequencing Genetics Humans Blinding eye Genetic Predisposition to Disease Gene Alleles Genetic Association Studies Genetics (clinical) Exome sequencing Disease gene Genetic heterogeneity Disease gene identification Phenotype 030104 developmental biology Amino Acid Substitution Deletion mutation Mutation |
| Zdroj: | Clinical Genetics. 94:554-563 |
| ISSN: | 1399-0004 0009-9163 |
| DOI: | 10.1111/cge.13426 |
| Popis: | Retinal dystrophies (RDs) are hereditary blinding eye conditions that are highly variable in their clinical presentation. The remarkable genetic heterogeneity that characterizes RD was a major challenge in establishing the molecular diagnosis in these patients until the recent advent of next-generation sequencing. It remains unclear, however, what percentage of autosomal recessive RD remain undiagnosed when all established RD genes are sequenced. We enrolled 75 families in which RD segregates in an apparently autosomal recessive manner. We show that the yield of a multigene panel that contains known RD genes is 67.5%. The higher yield (82.3%) when whole exome sequencing was implemented instead was often due to hits in genes that were not included in the original design of the panel. We also show the value of homozygosity mapping even during the era of exome sequencing in uncovering cryptic mutations. In total, we describe 45 unique likely deleterious variants (of which 18 are novel including one deep intronic and one genomic deletion mutation). Our study suggests that the genetic heterogeneity of autosomal recessive RD is approaching saturation and that any new RD genes will probably account for only a minor role in the mutation burden. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text