Parental mosaicism detection and preimplantation genetic testing in families with multiple transmissions of de novo mutations

Abstract

BackgroundDe novo mutations (DNMs) are linked with many severe early-onset disorders ranging from rare congenital malformation to intellectual disability. Conventionally, DNMs are considered to have an estimated recurrence rate of 1%. Recently, studies have revealed a higher prevalence of parental mosaicism, leading to a greater recurrence risk, resulting in a second child harbouring the same DNM as a previous child.MethodsIn this study, we included 10 families with DNMs leading to adverse pregnancy outcomes. DNA was extracted from tissue samples, including parental peripheral blood, parental saliva and paternal sperm. High-throughput sequencing was used to screen for parental mosaicism with a depth of more than 5000× on average and a variant allele fraction (VAF) detection limit of 0.5%.ResultsThe presence of mosaicism was detected in sperms in two families, with VAFs of 2.8% and 2.5%, respectively. Both families have a history of multiple adverse pregnancies and DNMs shared by siblings. Preimplantation genetic testing (PGT) and prenatal diagnosis were performed in one family, thereby preventing the reoccurrence of DNMs.ConclusionThis study is the first to report the successful implementation of PGT for monogenic/single gene defects in the parental mosaicism family. Our study suggests that mosaic detection of paternal sperm is warranted in families with recurrent DNMs leading to adverse pregnancy outcomes, and PGT can effectively block the transmission of the pathogenic mutation.

Identification of two novel and one rare mutation in DYRK1A and prenatal diagnoses in three Chinese families with intellectual Disability-7

“…To date, the majority of reported MRD7 patients have been sporadic cases resulting from a de novo pathogenic variant of the DYRK1A gene ( Hamdan et al, 2014 ). With accordingly negligible risks of recurrence, apparent de novo mutations have been reckoned as the primary occurrences for germline or zygotic incidents ( Xu et al, 2023 ). Nevertheless, for the pathogenic variant, those with a high ratio are truly inherited from a parent mosaic of which there is little evidence to prove.…”

ITPR1-associated spinocerebellar ataxia with craniofacial features—additional evidence for germline mosaicism

“…These pathogenic variants may occur post-zygotically during meiosis, but may also occur spontaneously over time (Thorpe et al 2020). Despite counseling families that the risk of recurrence in future pregnancies is approximately 1% following the birth of a child with a de novo variant, germline mosaicism is often not suspected until a second child with the same variant is born (Xu et al 2023;Frisk et al 2022).…”

Parental mosaicism rather than de novo variants in FOXG1‐related syndrome and TUBA1A‐associated Tubulinopathy: Familial case reports

“…De novo variants account for 48%–63% of deleterious variants detected in fetuses with structural abnormalities (Xu et al., 2023 ). The condition of mosaicism is frequently overlooked because of this high percentage.…”