Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0178776
Title: Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling
Authors: Tomar S. 
Sethi R. 
Sundar G.
Quah T.C. 
Quah B.L. 
Lai P.S. 
Keywords: cysteine
guanine
tyrosine
retinoblastoma protein
adult
allele
amino acid substitution
Article
blood sampling
cancer risk
controlled study
female
gene
gene deletion
gene mutation
genetic counseling
genetic screening
human
major clinical study
male
missense mutation
multiplex ligation dependent probe amplification
mutation rate
mutational analysis
patient care
phenotype
point mutation
RB1 gene
retinoblastoma
Singapore
DNA methylation
genetics
infant
pedigree
point mutation
preschool child
retinoblastoma
Child, Preschool
DNA Methylation
Female
Genetic Counseling
Humans
Infant
Male
Pedigree
Point Mutation
Retinoblastoma
Retinoblastoma Protein
Singapore
Issue Date: 2017
Citation: Tomar S., Sethi R., Sundar G., Quah T.C., Quah B.L., Lai P.S. (2017). Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling. PLoS ONE 12 (6) : e0178776. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0178776
Abstract: Retinoblastoma (RB) is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA) assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59) while only 42.4% (25/59) of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9%) of tumors screened. There were 3 cases (5.1%) in which no mutations could be detected and germline mutations were detected in 19.5% (8/41) of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59) of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variantc. 607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and asymptomatic family members carrying low-penetrance, germline mosaicism or heritable unilateral mutational phenotypes. © 2017 Tomar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161192
ISSN: 19326203
DOI: 10.1371/journal.pone.0178776
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