Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Abstract

Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1–2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)—that could be quantified in semen for paternal cases (recurrence risks of 5.6–12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.

BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome

“…Reagents and conditions were used as previously described. 22 Sample relationships in Family 2 were confirmed by a single molecule molecular inversion probe assay 23 using a panel of 47 informative biallelic SNPs.…”

Isolated dentinogenesis imperfecta: Novel DSPP variants and insights on genetic counselling

“…Therefore, parents were advised to seek psychological help for for their affected children which is empirical in these cases [ 27 ]. On the contrary, the outcome of genetic counseling of Family 2 was very positive as parents were very happy when informed that neither of them carries the DSPP variant and that the recurrence risk has decreased from 50% in each pregnancy to less than 1–2% [ 28 ]. However, we are aware that parental gonadal mosaicism was not ruled out in this family.…”

Assessment of parental mosaicism rates in neurodevelopmental disorders caused by apparent de novo pathogenic variants using deep sequencing

“…Because of their early onset during embryo development, type IIIA variants are usually observed across multiple tissues of the individuals, notably within the blood cells, and are at high risk of transmission to the offspring. In a medical setting, after the identification of a pathogenic DNV in a child, detecting type III mosaicism may therefore be relevant for genetic counselling given the higher risk of recurrence in a future pregnancy 6 . In addition, because of parental biological sample availability, it appears much more likely to detect type IIIA than type IIIB DNVs, which require the analysis of germinal cells.…”

“…Applying adapted bioinformatics procedures, from 0.3 to 3.4% of DNVs were found to be parental mosaics 8 – 12 . Specific protocols have also been used to detect parental blood mosaicism using more sensitive techniques on smaller cohorts, including amplicon-based targeted NGS 6 , 13 – 15 , digital-droplet PCR (ddPCR) 16 , 17 or single molecule molecular inversion probe (smMIP)-based targeted sequencing 18 , 19 . These various protocols influenced the prevalence of parental mosaicism by increasing the sensitivity to detect parental mosaics, allowing the detection of mosaics with lower allelic ratios.…”