The effect of parental origin of RB1 mutations in hereditary retinoblastoma with low penetrance

Background. In hereditary retinoblastoma, a germline mutation in one of the alleles of the RB1 gene causes a predisposition to the disease and its transmission within the pedigree. Hereditary retinoblastoma manifests at an earlier age compared with the sporadic form and in most cases is multifocal and bilateral. However, some families with retinoblastoma (two or more carriers of the same germline mutation in the pedigree) exhibit a milder phenotype with incomplete penetrance (some carriers of the germline mutation are asymptomatic) and variable expressivity (the same mutation in different family members may manifest as either a unilateral or bilateral form). Identification of low-penetrant mutations in the RB1 gene and studying their inheritance in pedigrees contributes to understanding the mechanisms underlying the development of retinoblastoma with low penetrance. It is extremely 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. Objective. To establish the spectrum of genetic disorders in the RB1 gene in Russian patients with hereditary retinoblastoma with incomplete penetrance and variable expressivity and to determine the effect of the parental origin of the RB1 mutation on its phenotypic manifestation. Methods. Using high-performance parallel sequencing, a molecular genetic survey of 332 unrelated patients with retinoblastoma was performed. Sanger sequencing was used to verify the identified point mutations and analyze their segregation in pedigrees. Results. In the group of patients without a family history of retinoblastoma, in 3.5% the hereditary nature of the disease was determined, where one of the parents was an asymptomatic carrier of a germline mutation in the RB1 gene. Ten low-penetrant mutations in the RB1 gene were identified. In 91.7% of cases of hereditary retinoblastoma with low penetrance, the mutant allele was obtained by a proband from a father with no clinical signs of the disease or with a milder form. Conclusion. The results confirm the previously suggested assumptions that low-penetrant germline mutations in the RB1 gene inherited from the father more often lead to the development of retinoblastoma, and in a more severe form than those inherited from the mother.

наследственная ретинобластома, ген RB1, пенетрантность, экспрессивность, высокопроизводительное параллельное секвенирование ДНК, низкопенетрантная мутация, hereditary retinoblastoma, RB1, penetrance, expressivity, NGS, low-penetrant mutation