Mosaicism and prenatal diagnosis options: insights from retinoblastoma

Abstract

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.

Figure 1

Likelihood of the germline hypothesis according to the observed data. Y-axis, left: probability P_H1 that the germline hypothesis fit the observed data, which depends on the proportion p₁ of mutated gametes in one of the two parents. Y-axis, right: ratio of the two P_H1 and P_H2 (developmental hypothesis) probabilities. The curve is based on our observations and the proposed hypotheses (see text for details).