Table 1.
Clinicopathological distribution of heritable and non-heritable retinoblastoma patients by laterality, age at diagnosis and family history.
Fig 1.
Age distribution of heritable and non-heritable RB cases.
The age distribution between Heritable-familial, Heritable-non familial and Non-Heritable RB cases was significant by Welch’s t test of unpaired groups (p = 0.001351; 95% CI [-22.4729, -5.7665]). Three cases had unknown age at diagnosis and hence not reflected.
Table 2.
Mutant RB1 alleles identified in all 59 RB cases.
Table 3.
Novel RB1 point mutations.
Table 4.
Recurrent RB1 point mutations.
Fig 2.
Incidence of germline and somatic RB1 point mutations in 50 RB cases.
A total of 61 RB1 point mutations were identified in 50 RB probands. The distribution of mutations by type of tumor (unilateral and bilateral) and whether they were detected in blood (germline) or only tumor (somatic) is shown.
Fig 3.
Distribution of total RB1 point mutations by Type.
The frequency of nonsense, frameshift, splice site, missense and promoter mutations among all the point mutations identified in our cohort.
Fig 4.
Schematic representation of sequence mutations across RB1 gene.
(GenBank Accession Number: L11910.1). The pocket domains are highlighted in orange (Pocket A) and purple (Pocket B) and exons are numbered respectively. Exons known to be mutational hotspots are highlighted with yellow boxes (Valverde et al 2005). Novel mutations are shown in callout boxes. Gross RB1 deletions are shown in blue for paternal loss of allele and pink for maternal loss of allele. Grey indicates unknown inheritance. The respective frequencies of gross RB1 deletions are given in brackets.
Table 5.
List of germline RB1 mutations identified in blood.
Table 6.
Spectrum of germline RB1 point mutations detected in blood of probands.
Table 7.
Germline mutations identified in this study that were previously reported as low-penetrance mutations.
Fig 5.
Pedigree of families with low penetrance and mosaic RB1 mutations.
Family F1: Father is a normal carrier of the heterozygous mutation: c.607+1G>T; Altered splicing. The proband and his younger brother carry the same heterozygous mutation and have unilateral RB. The proband also had an elder deceased sibling. Family F2: Father is an unaffected carrier of the heterozygous mutation: c.1981C>T; p.Arg661Trp. The proband and his brother have bilateral RB and carry the same heterozygous mutation. Family F3: The proband with unilateral RB carries a homozygous mutation: c.940-1G>C (altered splicing) in tumor. Only 4% of the proband’s blood leukocytes tested positive for the mutation (mosaicism). Both parents tested negative for the given mutation. Family F4: The proband with unilateral RB carries a homozygous mutation: c.958C>T; p.Arg320* in tumor. Only 2% of the proband’s blood leukocytes tested positive for the given mutation (mosaicism). Both parents tested negative for the given mutation. Family F5: The proband with unilateral RB has a deletion of one copy of RB1 allele in tumor and a mosaicism for the same mutation in blood, as only 60% blood leukocytes carried the given mutation. Both parents tested negative for the given mutation. Genotype is provided for tested members as m/m for homozygous carriers, m/+ for heterozygous carriers and +/+ for homozygous wild-type. Blackened symbols: bilateral RB; half-blackened symbols: unilateral RB; diagonally blackened symbol: Unknown Laterality of RB; dotted symbols: unaffected carriers; dashed symbols: deceased.
Table 8.
Germline mutations identified in this study that were reported as mosaic mutations.
Table 9.
List of somatic RB1 point mutation identified only in tumor cells.
Table 10.
Spectrum of somatic RB1 point mutations detected only in retinoblastoma tumors in Singaporean cohort.
Table 11.
Parental origin of allelic loss.