Retinoblastoma - Genetic Counseling and Molecular Diagnosis

Houdayer, Claude; Gauthier‐Villars, Marion; Castéra, Laurent; Desjardins, Laurence; Doz, François; Stoppa‐Lyonnet, Dominique

doi:10.5772/34069

Cited by 8 publications

(5 citation statements)

References 47 publications

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“…In-depth understanding of RB therefore requires large-scale genotype-phenotype studies. However, previous genotype-phenotype studies [13][14][15][16][17][18][19][20] have mainly been based on series of selected families or were derived from variant screening series comprising a limited number of patients with RB. In addition, large registry-based studies [21][22][23][24][25][26][27][28][29] lack detailed ocular and genotype descriptions and mainly focus on survival and treatment issues.…”

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confidence: 99%

Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma

et al. 2020

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IMPORTANCE Retinoblastoma (RB) is the most common pediatric intraocular neoplasm. RB is a complex model in which atypical pathogenic variants, modifier genes, imprinting, and mosaicism are known to be associated with the phenotype. In-depth understanding of RB therefore requires large genotype-phenotype studies.OBJECTIVE To assess the association between genotype and phenotype in patients with RB.

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confidence: 99%

Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma

et al. 2020

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“…The frequency of heterozygous people, carrying a RB1 pathogenic variant, is estimated between 1/15 000 and 1/20 000 in the general population. 5,7 Among the heterozygous population, 30% have bilateral Rb with no familial history, which provides a probability p 2 of being heterozygous due to a de novo pathogenic variant and developing a bilateral Rb equal to 1/20 000 × 0.3 = 1.5 × 10 − 5 . Hence, according to the developmental hypothesis, the probability to observe one recurrence in the 123 sibships is…”

Section: Resultsmentioning

confidence: 99%

“…Overall, and taking into account that the recurrence risk due to a de novo pathogenic variant is p 2 = 1.5 × 10 − 5 , we conclude that the recurrence risk for unaffected parents of bilateral Rb sporadic cases, due to mosaicism, can be estimated as 266-533-fold higher, as compared with the general population (0.004/p 2 to 0.008/p 2 ). These values justify surveillance protocols in use for retinoblastoma 5 and provides geneticists with reliable recurrence risks that could be helpful in counseling couples for prenatal diagnostic options. We believe this evaluation method or even this recurrence risk could be considered in other diseases with a high de novo mutation rate and should be used for genetic counseling and especially for improved prenatal options.…”

Section: Discussionmentioning

confidence: 99%

“…More specifically, sporadic bilateral retinoblastoma stems from an early post-zygotic mutation in the affected child (ie no recurrence risk in siblings) or a pre-zygotic mutation in an unaffected parent (ie undetermined recurrence risk in siblings). [2][3][4][5] Consequently, it represents a highly relevant model to better estimate the relative contribution of pre-and post-zygotic events and thereby recurrence risks in offspring.…”

Section: Introductionmentioning

confidence: 99%

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Mosaicism and prenatal diagnosis options: insights from retinoblastoma

et al. 2016

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In sporadic cases, a post-zygotic mutational event signifies a somatic mosaicism in the affected child only, which implies that these mutations affect only a portion of the body. Therefore siblings do not need follow-up. On the other hand, a pre-zygotic mutation transmitted by an unaffected mosaic parent implies recurrent risks in offspring. To better estimate the contribution of pre-and post-zygotic events, we analysed 124 consecutive bilateral retinoblastoma probands, carrying a heterozygous RB1 pathogenic variant and their unaffected, non-carrier parents. In order to evaluate somatic mosaicism in blood, the deleterious RB1 pathogenic variant identified in the proband, was searched for in the unaffected parents, using targeted deep sequencing. Observed recurrences, which represent an estimation of germline and somatic mosaicisms, were recorded and computed in the sibships. Deep sequencing revealed one mosaic-unaffected parent out of 124 tested couples, which provides an estimation of the maximal risk of recurrence, due to parental mosaicism, at 0.4%. Follow-up in the sibships showed one recurrence, providing a maximal recurrence risk, due to parental mosaicism, at 0.8%. Two different statistical strategies led to close estimates (0.4 and 0.8% risks) which appeared 266-533-fold higher, as compared with the general population. These recurrence estimates could be considered when counselling couples with retinoblastoma or diseases with a high de novo mutation rate.

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“…This small number is surprising, as the de novo mutation rate can be as high as 11-25% in APC, 74% in NF1 and up to 90% in RB1. [16][17][18] The present study estimated the BRCA1/2 de novo mutation rate in a large series of consecutive unrelated patients-that is, the proportion of BRCA1/2-mutated breast and ovarian cancer cases that were caused by de novo mutations.…”

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confidence: 99%

Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations

et al. 2015

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BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

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Retinoblastoma - Genetic Counseling and Molecular Diagnosis

Cited by 8 publications

References 47 publications

Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma

Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma

Mosaicism and prenatal diagnosis options: insights from retinoblastoma

Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations

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