Multiple transmissions of de novo mutations in families

• Published in: Nature genetics Vol. 50; no. 12; pp. 1674 - 1680
• Main Authors: Jónsson, Hákon, Sulem, Patrick, Arnadottir, Gudny A., Pálsson, Gunnar, Eggertsson, Hannes P., Kristmundsdottir, Snaedis, Zink, Florian, Kehr, Birte, Hjorleifsson, Kristjan E., Jensson, Brynjar Ö., Jonsdottir, Ingileif, Marelsson, Sigurdur Einar, Gudjonsson, Sigurjon Axel, Gylfason, Arnaldur, Jonasdottir, Adalbjorg, Jonasdottir, Aslaug, Stacey, Simon N., Magnusson, Olafur Th, Thorsteinsdottir, Unnur, Masson, Gisli, Kong, Augustine, Halldorsson, Bjarni V., Helgason, Agnar, Gudbjartsson, Daniel F., Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2018; Nature Publishing Group
• Subjects: 45; 45/22; 45/23; 45/56; 631/136/2434/1706; 631/136/2434/1822; 631/208/1516/1510; 631/208/2489/1512; 631/208/457; Adult; Agriculture; Analysis; Animal Genetics and Genomics; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Child; Children; Disease; Diseases; Embryonic Germ Cells - metabolism; Family; Family Characteristics; Female; Gene Function; Gene mutations; Genomes; Germ cells; Germ-Line Mutation; Haplotypes; Health aspects; Human Genetics; Humans; Inheritance Patterns - genetics; Letter; Male; Mosaicism; Muscular dystrophy; Mutation; Parent-Child Relations; Parents & parenting; Pedigree; Rare diseases; Relapse; Siblings; Iceland
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-018-0259-9

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. Analysis of 1,007 sibling pairs from 251 families identifies 878 de novo mutations shared by siblings at 448 sites. Recurrence probability based on parental somatic mosaicism, sibling sharing, parent of origin, mutation type and genomic position can range from 0.011% to 28.5%.