Novel RB1 germline mutation in a healthy man

Area of Science:

• Ophthalmology
• Genetics
• Oncology

Background:

• Retinoblastoma (Rb) is often unilateral and sporadic, but germline mutations in RB1 account for up to 40% of cases.
• Inherited RB1 mutations typically exhibit high penetrance, but the spectrum is heterogeneous, with limited data on unaffected carriers.
• Classifying RB1 mutations aids genetic counseling and screening, yet challenges remain due to the wide variability of the disease.

Observation:

• A five-month-old patient diagnosed with retinoblastoma was studied within a five-member Mexican family.
• Next-generation sequencing of the RB1 gene was performed on all family members.
• Comprehensive ophthalmological examinations were conducted on mutation-positive individuals.

Findings:

• The father and his infant daughter carried the novel non-synonymous RB1 mutation c.459del (p.Lys154Serfs*21).
• The daughter presented with bilateral retinoblastoma, successfully treated with chemotherapy and cryotherapy.
• The father, a carrier of the mutation, showed no ocular or imaging abnormalities, indicating low penetrance.

Implications:

• This case reveals a rare instance of a low-penetrance RB1 germline mutation.
• Long-term monitoring of the father includes ocular surveillance and screening for secondary malignancies.
• Further research is crucial to understand the implications for unaffected carriers of RB1 mutations.