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Condition report · Cancer

Hereditary Retinoblastoma

Whole genome sequencing identifies all RB1 variant types (including mosaic mutations that standard blood-based testing may miss) and resolves the germline vs. somatic question that determines lifetime cancer surveillance needs.

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About this condition

An inherited form of retinoblastoma, an eye cancer of early childhood, caused by germline variants in RB1. It often affects both eyes and raises the risk of other cancers later in life, such as sarcomas and melanoma.

Retinoblastoma (Rb) is the most common intraocular malignancy of childhood, affecting approximately 1 in 15,000-20,000 live births, with approximately 8,000 new cases diagnosed annually worldwide. It arises from retinoblasts (immature precursor cells of the retina) due to biallelic inactivation of the RB1 tumor suppressor gene on chromosome 13q14.2. RB1 was the first tumor suppressor gene characterized at the molecular level. Retinoblastoma presents with leukocoria (white pupillary reflex), strabismus, and vision loss, usually in children under 5 years. With current treatment, overall survival exceeds 95% in high-income countries, though outcomes vary substantially by disease stage and resource availability.

Approximately 40% of retinoblastoma cases are hereditary, caused by a germline (constitutional) pathogenic variant in RB1. Hereditary retinoblastoma is typically bilateral (75-80%) or multifocal, with median age of diagnosis younger than sporadic cases. The remaining ~60% of cases are sporadic (non-hereditary), caused by two somatic RB1 hits in a single retinal cell. Unilateral retinoblastoma may be hereditary or sporadic: approximately 15% of unilateral cases have germline RB1 variants, a proportion that rises to nearly 100% in bilateral cases. Approximately 10-15% of unilateral retinoblastoma without a detectable germline variant carry somatic mosaic RB1 mutations detectable only in tumor or in deep blood sequencing.

The critical distinction between hereditary and non-hereditary retinoblastoma lies not in the eye tumor prognosis, but in lifetime second cancer risk. Hereditary RB1 carriers have an estimated 50% cumulative risk of a second primary cancer by age 50, predominantly radiation-field related osteosarcomas, soft tissue sarcomas, and melanoma. This risk is substantially elevated by radiation therapy, which is avoided where possible in germline RB1 carriers. Surviving hereditary retinoblastoma triggers a lifetime surveillance protocol: regular imaging for soft tissue and bone tumors, avoidance of UV radiation, and cascade genetic testing of offspring with ophthalmic examination in infancy. Gene therapy and targeted RB1 pathway approaches are under investigation.

Mosaic RB1 mutations (where the germline variant is present in only a fraction of cells) occur in approximately 10-12% of hereditary retinoblastoma and may be missed by standard blood-based sequencing. Deep sequencing and tumor tissue analysis improve detection.

The condition we analyse

Autosomal dominant

Retinoblastoma due to a germline RB1 variant, typically bilateral or multifocal, with increased risk of second primary cancers.

What a diagnosis changes

Intra-arterial chemotherapy; intravitreous melphalan; systemic chemotherapy; enucleation for advanced cases; avoid radiation in confirmed germline RB1 carriers; lifetime second primary cancer surveillance (imaging, dermatology)

Genes analysed

Also known as

familial retinoblastoma; RB1; RB1-related retinoblastoma predisposition; retinoblastoma, autosomal dominant, somatic mutation; retinoblastoma, trilateral, autosomal dominant, somatic mutation

MONDO:0018160OMIM 180200Orphanet 357027MedGen 155869

Why whole genome sequencing

Determining germline vs. somatic mosaic RB1 status requires both blood and tumor tissue analysis at sequencing depths standard panels may not achieve. Mosaic variants in blood at 5-20% allele fraction are missed by conventional testing.

Mosaic RB1 variants are missed by standard germline testing, and have clinical consequences for the entire family

Somatic mosaicism in retinoblastoma, where the RB1 pathogenic variant arose post-zygotically and is present in only a subset of cells, affects approximately 10-12% of hereditary cases. Parents of an index patient with mosaic RB1 may themselves have mosaicism at very low variant allele fractions. Standard exome and panel sequencing is calibrated for germline heterozygous variants at ~50% allele fraction; mosaic variants present at 10-20% may fall below the variant calling threshold. Deep whole genome sequencing with enhanced sensitivity for low-allele-fraction variants improves mosaic detection. Missing a mosaic germline RB1 variant in a parent would lead to incorrect recurrence risk counseling, presenting the next pregnancy as no-risk when in fact the parent can transmit the variant.

Germline RB1 status determines radiation therapy decisions during tumor treatment

External beam radiation therapy for retinoblastoma substantially increases second primary cancer risk in germline RB1 carriers in the radiation field, particularly osteosarcoma of the orbital region. For this reason, current management of hereditary retinoblastoma strongly favors non-radiation-based approaches (intra-arterial chemotherapy, intravitreous melphalan, focal treatments) when feasible, specifically to avoid the radiation-associated second cancer risk. Making this treatment decision requires knowing germline RB1 status at the time of initial treatment, not years later when a second cancer develops. Whole genome sequencing provides the complete RB1 genotype, including mosaic detection, to inform treatment planning from day one.

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