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Multiple transmissions of de novo mutations in families

Authors :
Unnur Thorsteinsdottir
Kari Stefansson
Hannes P. Eggertsson
Hakon Jonsson
Daniel F. Gudbjartsson
Brynjar O. Jensson
Snaedis Kristmundsdottir
Gunnar K. Pálsson
Arnaldur Gylfason
Gudny A. Arnadottir
Ingileif Jonsdottir
Kristjan E. Hjorleifsson
Bjarni V. Halldorsson
Simon N. Stacey
Birte Kehr
Augustine Kong
S E Marelsson
Olafur Th Magnusson
Agnar Helgason
Patrick Sulem
Sigurjon A. Gudjonsson
Adalbjorg Jonasdottir
Gisli Masson
Florian Zink
Source :
Nature Genetics. 50:1674-1680
Publication Year :
2018
Publisher :
Springer Science and Business Media LLC, 2018.

Abstract

De novo mutations (DNMs) cause a large proportion of severe rare diseases of childhood. DNMs that occur early may result in mosaicism of both somatic and germ cells. Such early mutations can cause recurrence of disease. We scanned 1,007 sibling pairs from 251 families and identified 878 DNMs shared by siblings (ssDNMs) at 448 genomic sites. We estimated DNM recurrence probability based on parental mosaicism, sharing of DNMs among siblings, parent-of-origin, mutation type and genomic position. We detected 57.2% of ssDNMs in the parental blood. The recurrence probability of a DNM decreases by 2.27% per year for paternal DNMs and 1.78% per year for maternal DNMs. Maternal ssDNMs are more likely to be T>C mutations than paternal ssDNMs, and less likely to be C>T mutations. Depending on the properties of the DNM, the recurrence probability ranges from 0.011% to 28.5%. We have launched an online calculator to allow estimation of DNM recurrence probability for research purposes.

Details

ISSN :
15461718 and 10614036
Volume :
50
Database :
OpenAIRE
Journal :
Nature Genetics
Accession number :
edsair.doi...........e848021e3f531dbe5ae743fbbda447d7