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Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling

Tomar, Swati ; Sethi, Raman ; Sundar, Gangadhara ; Quah, Thuan Chong ; Quah, Boon Long ; Lai, Poh San Cai, Tao

PloS one, 2017-06, Vol.12 (6), p.e0178776-e0178776 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling
Autor: Tomar, Swati ; Sethi, Raman ; Sundar, Gangadhara ; Quah, Thuan Chong ; Quah, Boon Long ; Lai, Poh San
Cai, Tao
Assuntos: Alternative splicing ; Amplification ; Assaying ; Biology and Life Sciences ; Blood ; Cancer ; Care and treatment ; Carriers ; Child, Preschool ; Children ; Combinatorial analysis ; Copy number ; Deactivation ; Deoxyribonucleic acid ; Development and progression ; Diagnosis ; Disease control ; DNA ; DNA Methylation ; Dosage ; Female ; Gene deletion ; Gene dosage ; Gene mutation ; Gene mutations ; Gene sequencing ; Genes ; Genetic aspects ; Genetic Counseling ; Genetic screening ; Genetic testing ; Health aspects ; Humans ; Inactivation ; Incidence ; Infant ; Male ; Medicine and Health Sciences ; Mosaicism ; Multiplexing ; Mutation ; Patients ; Pediatrics ; Pedigree ; Peripheral blood ; Point Mutation ; Research and Analysis Methods ; Retina ; Retinoblastoma ; Retinoblastoma - genetics ; Retinoblastoma - therapy ; Retinoblastoma protein ; Retinoblastoma Protein - genetics ; Risk ; Screening ; Singapore ; Tumors
É parte de: PloS one, 2017-06, Vol.12 (6), p.e0178776-e0178776
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Conceptualization: GS TCQ BLQ PSL.Funding acquisition: PSL.Investigation: ST RS GS BLQ TCQ PSL.Methodology: GS TCQ BLQ PSL.Resources: BLQ GS TCQ PSL.Supervision: PSL.Visualization: ST RS.Writing – original draft: ST PSL.Writing – review & editing: ST RS GS BLQ TCQ PSL.
Competing Interests: The authors have declared that no competing interests exist.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling

Tomar, Swati ; Sethi, Raman ; Sundar, Gangadhara ; Quah, Thuan Chong ; Quah, Boon Long ; Lai, Poh San Cai, Tao

United States: Public Library of Science

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