RB1 – Retinoblastoma

Retinoblastoma is a pediatric intraocular malignancy initiated by germline or somatic loss-of-function variants in the RB1 tumor suppressor gene. Germline RB1 variants follow an autosomal dominant inheritance mode with high penetrance; however, rare low-penetrance alleles yield incomplete expressivity and variable laterality (PMID:8651278). Biallelic inactivation of RB1 in retinal progenitor cells triggers tumorigenesis, underscoring its critical role in cell cycle control.

Genetic evidence includes over 200 distinct germline RB1 variants reported in 180 unrelated patients, encompassing nonsense, frameshift, splice, and missense mutations across all exons (PMID:15884040). Familial segregation analyses demonstrate co-segregation of pathogenic alleles with disease in multiple pedigrees, and somatic second-hit events confirm RB1 as the causative locus. Recurrent C→T transitions at CGA Arg codons, notably c.1981C>T (p.Arg661Trp), account for a significant proportion of truncating alleles (PMID:1352883).

Functional studies elucidate a haploinsufficiency mechanism in which loss of pRB impairs E2F repression, disrupts G1/S checkpoint fidelity, and alters transcriptional repression of growth-promoting genes. Wild-type pRB—but not its inactivating mutants—represses interleukin-6 and c-fos promoters, and RB1 loss leads to unchecked proliferation in cell and animal models (PMID:1652755). Temperature-sensitive and low-penetrance alleles retain partial pocket function and subnuclear localization, correlating with milder phenotypes (PMID:9342358).

Genotype-phenotype correlations reveal that null alleles typically cause bilateral disease with near-complete penetrance, whereas missense and promoter mutations exhibit reduced expressivity and later onset. Low-penetrance families highlight the value of transcript and minigene assays to resolve variant pathogenicity when conventional sequencing is ambiguous.

No credible conflicting data dispute the RB1–retinoblastoma association. The integration of comprehensive genetic testing, family segregation analysis, and functional assays underpins a Definitive clinical validity classification.

Key Take-home: Germline RB1 inactivation follows an autosomal dominant pattern and is Definitively associated with retinoblastoma; genetic and functional assays are essential for accurate diagnosis, risk prediction, and management.

References

• American Journal of Human Genetics • 1996 • The spectrum of RB1 germ-line mutations in hereditary retinoblastoma PMID:8651278
• Human Mutation • 2005 • Sensitive multistep clinical molecular screening of 180 unrelated individuals with retinoblastoma detects 36 novel mutations in the RB1 gene PMID:15884040
• Proceedings of the National Academy of Sciences of the United States of America • 1992 • Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype PMID:1352883
• Proceedings of the National Academy of Sciences of the United States of America • 1997 • Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function PMID:9342358
• Proceedings of the National Academy of Sciences of the United States of America • 1991 • Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product PMID:1652755

Evidence Based Scoring (AI generated)