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Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results
- Source :
- Orphanet Journal of Rare Diseases, Vol 15, Iss 1, Pp 1-11 (2020), Orphanet Journal of Rare Diseases
- Publication Year :
- 2020
- Publisher :
- BMC, 2020.
-
Abstract
- Background 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. Results 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. Conclusions 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.
- Subjects :
- 0301 basic medicine
PRPF31
ABCA4
lcsh:Medicine
DNA sequencing
Frameshift mutation
03 medical and health sciences
0302 clinical medicine
Inherited retinal diseases
Gene therapy
Exome Sequencing
medicine
Humans
Exome
Pharmacology (medical)
Genetic Testing
Eye Proteins
Genetics (clinical)
Exome sequencing
Genetic testing
Whole genome sequencing
Genetics
Comparative Genomic Hybridization
medicine.diagnostic_test
biology
Research
lcsh:R
Whole exome sequencing
General Medicine
Human genetics
3. Good health
030104 developmental biology
Fundoscopy
030221 ophthalmology & optometry
biology.protein
ATP-Binding Cassette Transporters
Retinitis Pigmentosa
Subjects
Details
- Language :
- English
- ISSN :
- 17501172
- Volume :
- 15
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Orphanet Journal of Rare Diseases
- Accession number :
- edsair.doi.dedup.....3d17efed1518726f1010a4f81f2d5b90