Novel, deep intronic RB1 variant exhibiting incomplete penetrance and a parent-of-origin effect

Identification of an inherited RB1 pathogenic variant facilitates earlier diagnosis and improved outcomes for patients and at-risk relatives. Inheritance risk estimates, screening recommendations, and prenatal decision-making are complicated by RB1 variant-specific incomplete penetrance and parent-of-origin effect. This case report highlights a novel, deep intronic RB1 c.2212-170A > G variant identified through whole genome sequencing in a family with retinoblastoma exhibiting incomplete penetrance and a parent-of-origin effect. RNA analysis confirmed retention of intronic sequence (exonization), leading to unstable mRNA and/or truncated RB protein. This variant and the associated family history add to the existing body of literature to improve diagnostic genetic testing, clarify inheritance risks, and improve long-term outcomes for retinoblastoma patients.