Mosaicism and risk prediction in parents of children with de novo variants (MORNOVA)

点击翻译按钮获取中文摘要

The aim of the present application is to investigate mosaicism in parents of children with a severe genetic disease due to a de novo variant with two molecular genetic methods and thus to be able to indicate the recurrence risk for siblings more precisely. Up to now, affected parents have been given a blanket estimate of a recurrence risk of less than 1 to 5 %. However, depending on the development of a de novo variant, this is between practically zero and 50% for a further child. We already have various tissue samples from 237 affected families. In these families, the origin of the variant (phasing) will be determined by nanopore sequencing and both parents will be analysed for mosaicism in different tissues by targeted panel analysis with unique molecular identifiers (UMI). These results will be used with other already available data on the emergence of de novo variants and clinically irrelevant variants (from the literature as well as in our cohort) to calculate the individual risk of recurrence. Furthermore, the data will be correlated and verified with trio-exome analyses in mouse families. Finally, the results will be integrated into the clinical routine and, in the long run, into the individual counselling of couples facing the question of invasive prenatal diagnostics in case of a new pregnancy.