Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree
Retinitis pigmentosa (RP) causes progressive photoreceptor loss resulting from mutations in over 80 genes. This study identified the genetic cause of RP in three members of a non-consanguineous pedigree. Detailed ophthalmic evaluation was performed in the three affected family members. Whole exome s...
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doaj-988cebd8de964cd6bc204bc7808f46f02020-11-24T21:44:57ZengMDPI AGGenes2073-44252017-08-018921010.3390/genes8090210genes8090210Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish PedigreeKevin Gustafson0Jacque L. Duncan1Pooja Biswas2Angel Soto-Hermida3Hiroko Matsui4David Jakubosky5John Suk6Amalio Telenti7Kelly A. Frazer8Radha Ayyagari9Ophthalmology, University of California, San Francisco, San Francisco, CA 94143-0730, USAOphthalmology, University of California, San Francisco, San Francisco, CA 94143-0730, USAREVA University, Bengaluru, Karnataka 560034, IndiaShiley Eye Institute, University of California, San Diego, La Jolla, CA 92093-0946, USABiomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USABiomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USAShiley Eye Institute, University of California, San Diego, La Jolla, CA 92093-0946, USAHuman Longevity, Inc., San Diego, CA 92121, USABiomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USAShiley Eye Institute, University of California, San Diego, La Jolla, CA 92093-0946, USARetinitis pigmentosa (RP) causes progressive photoreceptor loss resulting from mutations in over 80 genes. This study identified the genetic cause of RP in three members of a non-consanguineous pedigree. Detailed ophthalmic evaluation was performed in the three affected family members. Whole exome sequencing (WES) and whole genome sequencing (WGS) were performed in the three affected and the two unaffected family members and variants were filtered to detect rare, potentially deleterious variants segregating with disease. WES and WGS did not identify potentially pathogenic variants shared by all three affected members. However, WES identified a previously reported homozygous nonsense mutation in KIZ (c.226C>T, p.Arg76*) in two affected sisters, but not in their affected second cousin. WGS revealed a novel 1.135 kb homozygous deletion in a retina transcript of C21orf2 and a novel 30.651 kb heterozygous deletion in CACNA2D4 in the affected second cousin. The sisters with the KIZ mutation carried no copies of the C21orf2 or CACNA2D4 deletions, while the second cousin with the C21orf2 and CACNA2D4 deletions carried no copies of the KIZ mutation. This study identified two independent, homozygous mutations in genes previously reported in autosomal recessive RP in a non-consanguineous family, and demonstrated the value of WGS when WES fails to identify likely disease-causing mutations.https://www.mdpi.com/2073-4425/8/9/210retinageneticsretinitis pigmentosa |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kevin Gustafson Jacque L. Duncan Pooja Biswas Angel Soto-Hermida Hiroko Matsui David Jakubosky John Suk Amalio Telenti Kelly A. Frazer Radha Ayyagari |
spellingShingle |
Kevin Gustafson Jacque L. Duncan Pooja Biswas Angel Soto-Hermida Hiroko Matsui David Jakubosky John Suk Amalio Telenti Kelly A. Frazer Radha Ayyagari Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree Genes retina genetics retinitis pigmentosa |
author_facet |
Kevin Gustafson Jacque L. Duncan Pooja Biswas Angel Soto-Hermida Hiroko Matsui David Jakubosky John Suk Amalio Telenti Kelly A. Frazer Radha Ayyagari |
author_sort |
Kevin Gustafson |
title |
Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree |
title_short |
Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree |
title_full |
Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree |
title_fullStr |
Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree |
title_full_unstemmed |
Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree |
title_sort |
whole genome sequencing revealed mutations in two independent genes as the underlying cause of retinal degeneration in an ashkenazi jewish pedigree |
publisher |
MDPI AG |
series |
Genes |
issn |
2073-4425 |
publishDate |
2017-08-01 |
description |
Retinitis pigmentosa (RP) causes progressive photoreceptor loss resulting from mutations in over 80 genes. This study identified the genetic cause of RP in three members of a non-consanguineous pedigree. Detailed ophthalmic evaluation was performed in the three affected family members. Whole exome sequencing (WES) and whole genome sequencing (WGS) were performed in the three affected and the two unaffected family members and variants were filtered to detect rare, potentially deleterious variants segregating with disease. WES and WGS did not identify potentially pathogenic variants shared by all three affected members. However, WES identified a previously reported homozygous nonsense mutation in KIZ (c.226C>T, p.Arg76*) in two affected sisters, but not in their affected second cousin. WGS revealed a novel 1.135 kb homozygous deletion in a retina transcript of C21orf2 and a novel 30.651 kb heterozygous deletion in CACNA2D4 in the affected second cousin. The sisters with the KIZ mutation carried no copies of the C21orf2 or CACNA2D4 deletions, while the second cousin with the C21orf2 and CACNA2D4 deletions carried no copies of the KIZ mutation. This study identified two independent, homozygous mutations in genes previously reported in autosomal recessive RP in a non-consanguineous family, and demonstrated the value of WGS when WES fails to identify likely disease-causing mutations. |
topic |
retina genetics retinitis pigmentosa |
url |
https://www.mdpi.com/2073-4425/8/9/210 |
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