Journal article
Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results
Orphanet journal of rare diseases, Vol.15(1), pp.32-32
01/30/2020
DOI: 10.1186/s13023-020-1312-1
PMCID: PMC6993391
PMID: 32000842
Abstract
Whole exome sequencing (WES) allows for an unbiased search of the genetic cause of a disease. Employing it as a first-tier genetic testing can be favored due to the associated lower incremental cost per diagnosis compared to when using it later in the diagnostic pathway. However, there are technical limitations of WES that can lead to inaccurate negative variant callings. Our study presents these limitations through a re-evaluation of negative WES results using subsequent tests primarily driven by fundoscopic findings. These tests included targeted gene testing, inherited retinal gene panels, whole genome sequencing (WGS), and array comparative genomic hybridization.
Subsequent genetic testing guided by fundoscopy findings identified the following variant types causing retinitis pigmentosa that were not detected by WES: frameshift deletion and nonsense variants in the RPGR gene, 353-bp Alu repeat insertions in the MAK gene, and large exonic deletion variants in the EYS and PRPF31 genes. Deep intronic variants in the ABCA4 gene causing Stargardt disease and the GUCY2D gene causing Leber congenital amaurosis were also identified.
Negative WES analyses inconsistent with the phenotype should raise clinical suspicion. Subsequent genetic testing may detect genetic variants missed by WES and can make patients eligible for gene replacement therapy and upcoming clinical trials. When phenotypic findings support a genetic etiology, negative WES results should be followed by targeted gene sequencing, array based approach or whole genome sequencing.
Details
- Title: Subtitle
- Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results
- Creators
- Ahra Cho - Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, Edward S. Harkness Eye Institute, New York, NY, USAJose Ronaldo Lima de Carvalho Jr - Department of Ophthalmology, Federal University of São Paulo (UNIFESP), São Paulo, BrazilAkemi J Tanaka - Department of Pathology & Cell Biology, and Columbia Stem Cell Initiative, Columbia University Medical Center, New York, NY, USARuben Jauregui - Weill Cornell Medical College, New York, NY, USASarah R Levi - Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, Edward S. Harkness Eye Institute, New York, NY, USAAlexander G Bassuk - Department of Pediatrics, University of Iowa, Iowa City, IA, USAVinit B Mahajan - Veterans Affairs Palo Alto Health Care Systems, Palo Alto, CA, USAStephen H Tsang - Department of Pathology & Cell Biology, and Columbia Stem Cell Initiative, Columbia University Medical Center, New York, NY, USA. sht2@cumc.columbia.edu
- Resource Type
- Journal article
- Publication Details
- Orphanet journal of rare diseases, Vol.15(1), pp.32-32
- DOI
- 10.1186/s13023-020-1312-1
- PMID
- 32000842
- PMCID
- PMC6993391
- NLM abbreviation
- Orphanet J Rare Dis
- ISSN
- 1750-1172
- eISSN
- 1750-1172
- Publisher
- England
- Language
- English
- Date published
- 01/30/2020
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984070162502771
Metrics
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