Retinoblastoma (RB) is the most common pediatric ocular tumor that occurs due to biallelic inactivation of the RB1 tumor suppressor gene. RB may be unilateral or bilateral and is hereditary in 50% of cases. Inactivation of the RB1 gene may occur by gross rearrangements (20%) or by small-length changes (80%): single nucleotide substitutions (SNVs) and insertions/deletions (INDELs). We analyzed the SNVs and INDELs of germinal origin, annotated in the database http://rb1-lovd.d-lohmann.de, in order to find the frequency of different variants, their correlation with the protein pRB functional domains and with the clinical presentation. The number of mutation variants analyzed was 2103, 34% of them were nonsense, 34% indels, 22% splice-site and 10% missense. All these variants mainly gave rise to bilateral RB (88%), their frequency and distribution in relation to pRB domains varied between bilateral (Bi) and unilateral hereditary (Ug) RB. Nonsense variants occurred more frequently in Bi vs Ug, whereas missense variants were more frequent in Ug vs Bi. Indels and Splice-site variants were not significantly different between Bi and Ug. The most frequent pRB location of mutation variants was in the Pocket domain (the binding site of the E2F transcription factor), 58% for nonsense, 64% missense, 50% splice site and 45% INDELs. The slice-site of the consensus sequence most mutated was the first nucleotide of the donor, which is the driver of the splicing process.

Conclusions The highest percentage of variants in RB corresponded to nonsense substitutions and indels, mainly affecting the Pocket domain, which is the major functional site for pRB regulatory process These results indicate the predominance of the most pathogenic variants in retinoblastoma.

The authors have declared no competing interest.

This study did not receive any funding

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Ethics Committee of Hospital de Clinicas Jose de San Martin Universidad de Buenos Aires Buenos Aires. Argentina gave ethical approval for this work.

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