- Authors:
-
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
- Title:
-
Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma
- Year:
-
2018
- Type of item:
-
Articolo in Rivista
- Tipologia ANVUR:
- Articolo su rivista
- Language:
-
Inglese
- Referee:
-
No
- Name of journal:
- European Journal of Human Genetics
- ISSN of journal:
- 1018-4813
- N° Volume:
-
26
- Number or Folder:
-
7
- Page numbers:
-
1026-1037
- Keyword:
-
Exons; Gene Expression Regulation, Neoplastic; Mosaicism; Mutation; Pedigree; Pregnancy; RNA Splicing; Retinoblastoma; Retinoblastoma Binding Proteins; Risk Factors; Ubiquitin-Protein Ligases; Young Adult; Genetic Counseling
- Short description of contents:
- 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.
- Web page:
-
https://doi.org/10.1038/s41431-017-0054-6
- Product ID:
-
128111
- Handle IRIS:
-
11562/1072343
- Last Modified:
-
February 23, 2023
- Bibliographic citation:
-
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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