RT Journal Article
SR Electronic
T1 Parental mosaicism detection and preimplantation genetic testing in families with multiple transmissions of de novo mutations
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 910
OP 917
DO 10.1136/jmg-2022-108920
VO 60
IS 9
A1 Naixin Xu
A1 Weihui Shi
A1 Xianling Cao
A1 Xuanyou Zhou
A1 Li Jin
A1 He-Feng Huang
A1 Songchang Chen
A1 Chenming Xu
YR 2023
UL http://jmg.bmj.com/content/60/9/910.abstract
AB Background De 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.Methods In 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%.Results The 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.Conclusion This 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.Data are available on reasonable request.