Parental Origin of the RB1 Gene Mutations in Families with Low Penetrance Hereditary Retinoblastoma

SIMPLE SUMMARY: Some families with hereditary retinoblastoma exhibit mild phenotype with low penetrance and variable expressivity, including complete absence of clinical signs of the disease in some carriers of the germline RB1 mutation. The identification of low-penetrance mutations in the RB1 gene and the study of their inheritance in pedigrees is contributing to understanding the mechanisms underlying the development of retinoblastoma with low penetrance. It is important both for further expansion of knowledge in the field of molecular genetics of retinoblastoma, and for competent genetic counseling and subsequent clinical management of families with this form of the disease. Our results support an assumption that parental origin of an RB1 mutation influences the likelihood of developing retinoblastoma. We also revealed a relatively high frequency of asymptomatic carriage of the RB1 mutations among the parents of retinoblastoma patients, highlighting the utmost necessity for molecular analysis among the probands’ relatives irrespective of their clinical status and family history of retinoblastoma. ABSTRACT: Our aim was to identify RB1 alterations causing hereditary low penetrance retinoblastoma and to evaluate how the parental origin of an RB1 mutation affects its phenotypic expression. By NGS and MLPA, RB1 mutations were found in 191 from 332 unrelated retinoblastoma patients. Among patients with identified RB1 mutations but without clinical family history of retinoblastoma, 7% (12/175) were found to have hereditary disease with one of the parents being an asymptomatic carrier of an RB1 mutation. Additionally, in two families with retinoblastoma history, mutations were inherited by probands from unaffected parents. Overall, nine probands inherited RB1 mutations from clinically unaffected fathers and five, from mothers. Yet, we gained explanations of maternal “unaffectedness” in most cases, either as somatic mosaicism or as clinical presentation of retinomas in involution, rendering the proportion of paternal to maternal truly asymptomatic mutation carriers as 9:1 (p = 0.005). This observation supports an assumption that parental origin of an RB1 mutation influences the likelihood of developing retinoblastoma. Additionally, our study revealed a relatively high frequency of asymptomatic carriage of the RB1 mutations among the parents of retinoblastoma patients, highlighting the utmost necessity of molecular analysis among the probands’ relatives irrespective of their clinical status and family history of retinoblastoma.