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An overview of RB1 transcript alterations detected during retinoblastoma genetic screening

Price, Elizabeth A; Sagoo, Mandeep S; Reddy, M Ashwin; Onadim, Zerrin; (2023) An overview of RB1 transcript alterations detected during retinoblastoma genetic screening. Ophthalmic Genetics pp. 1-11. 10.1080/13816810.2023.2270570. (In press).

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Abstract

Identification of pathogenic RB1 variants aids in the clinical management of families with retinoblastoma. We routinely screen DNA for RB1 variants, but transcript analysis can also be used for variant screening, and to help decide variant pathogenicity. DNA was screened by conformation analysis followed by Sanger sequencing. Large deletion/insertions were detected by polymorphism analysis, MLPA and quantitative-PCR. Methylation-specific PCR was used to detect hypermethylation. RNA screening was performed when a DNA pathogenic variant was missing, or to determine effects on splicing.Two hundred and thirteen small coding variants were predicted to affect splicing in 207 patients. Splice donor (sd) variants were nearly twice as frequent as splice acceptor (sa) with the most affected positions being sd + 1 and sa-1. Some missense and nonsense codons altered splicing, while some splice consensus variants did not. Large deletion/insertions can disrupt splicing, but RNA analysis showed that some of these are more complex than indicated by DNA testing. RNA screening found pathogenic variants in 53.8% of samples where DNA analysis did not. RB1 splicing is altered by changes at consensus splice sites, some missense and nonsense codons, deep intronic changes and large deletion/insertions. Common alternatively spliced transcripts may complicate analysis. An effective molecular screening strategy would include RNA analysis to help determine pathogenicity.

Type: Article
Title: An overview of RB1 transcript alterations detected during retinoblastoma genetic screening
Location: England
DOI: 10.1080/13816810.2023.2270570
Publisher version: http://dx.doi.org/10.1080/13816810.2023.2270570
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: genetic, pathogenic, RB1, Retinoblastoma, splicing, transcript
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10183732
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