Pubblicazioni

Autori:

Imperatore, Valentina; Pinto, Anna Maria; Gelli, Elisa; Trevisson, Eva; Morbidoni, Valeria; Frullanti, Elisa; Hadjistilianou, Theodora; De Francesco, Sonia; Toti, Paolo; Gusson, Elena; Roversi, Gaia; Accogli, Andrea; Capra, Valeria; Mencarelli, Maria Antonietta; Renieri, Alessandra; Ariani, Francesca

Titolo:

Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma

Anno:

2018

Tipologia prodotto:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Lingua:

Inglese

Referee:

No

Nome rivista:

European Journal of Human Genetics

ISSN Rivista:

1018-4813

N° Volume:

26

Numero o Fascicolo:

7

Intervallo pagine:

1026-1037

Parole chiave:

Exons; Gene Expression Regulation, Neoplastic; Mosaicism; Mutation; Pedigree; Pregnancy; RNA Splicing; Retinoblastoma; Retinoblastoma Binding Proteins; Risk Factors; Ubiquitin-Protein Ligases; Young Adult; Genetic Counseling

Breve descrizione dei contenuti:

Retinoblastoma is the most common eye cancer in children. Numerous families have been described displaying reduced penetrance and expressivity. An extensive molecular characterization of seven families led us to characterize the two main mechanisms impacting on phenotypic expression, as follows: (i) mosaicism of amorphic pathogenic variants; and (ii) parent-of-origin-effect of hypomorphic pathogenic variants. Somatic mosaicism for RB1 splicing variants (c. 1960+ 5G> C and c. 2106+ 2T>C), leading to a complete loss of function was demonstrated by high-depth NGS in two families. In both cases, the healthy carrier parent (one with retinoma) showed a variant frequency lower than that expected for a heterozygous individual, indicating a 56-60% mosaicism level. Previous evidences of a similar to 3-fold excess of RB1 maternal canonical transcript led us to hypothesize that this differential allelic expression could influence phenotypic outcome in families at risk for RB onset. Accordingly, in five families, we identified a higher tumor risk associated with paternally inherited hypomorphic pathogenic variants, namely a deletion resulting in the loss of 37 amino acids at the N-terminus (c. 60816_608del), an exonic substitution with a "leaky" splicing effect (c. 1331A>G), a partially deleterious substitution (c. 1981C>T) and a truncating C-terminal variant (c. 2663+ 2T>C). The identification of these mechanisms changes the genetic/prenatal counseling and the clinical management of families, indicating a higher recurrence risk when the hypomorphic pathogenic variant is inherited from the father, and suggesting the need for second tumor surveillance in unaffected carriers at risk of developing adult-onset cancer such as osteosarcoma or leiomyosarcoma.

Pagina Web:

https://doi.org/10.1038/s41431-017-0054-6

Id prodotto:

128111

Handle IRIS:

11562/1072343

ultima modifica:

23 febbraio 2023

Citazione bibliografica:

Imperatore, Valentina; Pinto, Anna Maria; Gelli, Elisa; Trevisson, Eva; Morbidoni, Valeria; Frullanti, Elisa; Hadjistilianou, Theodora; De Francesco, Sonia; Toti, Paolo; Gusson, Elena; Roversi, Gaia; Accogli, Andrea; Capra, Valeria; Mencarelli, Maria Antonietta; Renieri, Alessandra; Ariani, Francesca, Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma «European Journal of Human Genetics» , vol. 26 , n. 7 , 2018 , pp. 1026-1037

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