LOW PENETRANCE RETINOBLASTOMA FAMILIES

DIANA PARMA; M. FERRER,; LEONELA LUCE; CARCIONE, MICAELA;; MAZZANTI, CHIARA; GILIBERTO FLORENCIA; SZIJAN I

Congreso; REUNIÓN ANUAL DE SOCIEDAD DE BIOCIENCIAS SAIC-SAI-AAFE-NANOMED.AR 2021 REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2021

LOW PENETRANCE RETINOBLASTOMA FAMILIESDiana Parma1, Marcela Ferrer2, Leonela Luce1, Micaela Carcione1, Chiara Mazzanti1, Florencia Giliberto1, Irene Szijan11. Cátedra de Genética, INIGEM, UBA-CONICET Buenos Aires2. Servicio de Genética, Hospital de Clínicas “José de San Martín” UBA Buenos AiresRetinoblastoma (RB), the most common eye pediatric neoplasm, results from biallelic inactivation of RB1 tumor suppressor gene. Predisposition to RB is transmitted as an autosomal dominant trait with 90% penetrance. However, some RB families included unaffected carriers indicating low penetrance (LP). Our aim was to study the families with LP retinoblastoma and detect the asymptomatic carriers. RB1 mutations were identified by sequencing, MLPA assay, and segregation of polymorphisms. We reviewed the analyses of 18 families, 15 of them segregated with high-penetrance (HP) mutations and 3 with low-penetrance (LP) mutations. In addition, 4 families with sporadic RB patients included unaffected mutation-carrier relatives. The HP families included 5 unilateral, 26 bilateral patients and 2 unaffected carriers, the mean diseased eye ratio (DER) was 1.74. The LP families included 27 germline carriers of which 8 were unilateral, 3 bilateral, 1 had retinoma, 1 was a mutation mosaic and 14 were unaffected, the mean DER was 0.54. The parental origin of mutant allele was documented in 20 germline carriers: 15 carriers received the mutation from their father and 5 from their mother. Seven carriers of father´s mutant allele were affected, 7 carriers were unaffected and 1 developed a retinoma. Four carriers of mother´s mutation developed RB and 1 was unaffected. The mutations identified in LP families were: 2 in promoter, 2 missense, 1 in splicing site and 1 RB1 gene deletion. These mutations cause less pRB protein or less functional pRB or decrease cell viability and tumor development. Our results show that the survey of 18 RB families and sporadic RB cases revealed 7 families with 14 unaffected mutation carriers, what indicates a LP of RB. Detection of unaffected carriers is of utmost importance to assess the risk to their offspring. The parental origin of LP mutations defines the penetrance of hereditary RB and allows to delve into molecular bases of LP retinoblastoma.