PMID- 28575107
OWN - NLM
STAT- MEDLINE
DCOM- 20170922
LR  - 20240327
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 6
DP  - 2017
TI  - Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with 
      implications for genetic management and counselling.
PG  - e0178776
LID - 10.1371/journal.pone.0178776 [doi]
LID - e0178776
AB  - 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 variant-c.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.
FAU - Tomar, Swati
AU  - Tomar S
AD  - Department of Paediatrics, Yong Loo Lin School of Medicine, National University 
      of Singapore, Singapore, Singapore.
FAU - Sethi, Raman
AU  - Sethi R
AD  - Department of Paediatrics, Yong Loo Lin School of Medicine, National University 
      of Singapore, Singapore, Singapore.
FAU - Sundar, Gangadhara
AU  - Sundar G
AD  - Department of Ophthalmology, National University Hospital, Singapore, Singapore.
FAU - Quah, Thuan Chong
AU  - Quah TC
AD  - Department of Paediatrics, Yong Loo Lin School of Medicine, National University 
      of Singapore, Singapore, Singapore.
FAU - Quah, Boon Long
AU  - Quah BL
AD  - Singapore National Eye Centre, Singapore, Singapore.
FAU - Lai, Poh San
AU  - Lai PS
AD  - Department of Paediatrics, Yong Loo Lin School of Medicine, National University 
      of Singapore, Singapore, Singapore.
LA  - eng
PT  - Journal Article
DEP - 20170602
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Retinoblastoma Protein)
SB  - IM
MH  - Child, Preschool
MH  - DNA Methylation
MH  - Female
MH  - *Genetic Counseling
MH  - Humans
MH  - Infant
MH  - Male
MH  - Pedigree
MH  - *Point Mutation
MH  - Retinoblastoma/*genetics/therapy
MH  - Retinoblastoma Protein/*genetics
MH  - Singapore
PMC - PMC5456385
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2017/06/03 06:00
MHDA- 2017/09/25 06:00
PMCR- 2017/06/02
CRDT- 2017/06/03 06:00
PHST- 2016/11/09 00:00 [received]
PHST- 2017/05/18 00:00 [accepted]
PHST- 2017/06/03 06:00 [entrez]
PHST- 2017/06/03 06:00 [pubmed]
PHST- 2017/09/25 06:00 [medline]
PHST- 2017/06/02 00:00 [pmc-release]
AID - PONE-D-16-44556 [pii]
AID - 10.1371/journal.pone.0178776 [doi]
PST - epublish
SO  - PLoS One. 2017 Jun 2;12(6):e0178776. doi: 10.1371/journal.pone.0178776. 
      eCollection 2017.