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Multiple transmissions of de novo mutations in families

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.

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Fig. 1: View of the ssDNM extraction.
Fig. 2: Germ cell lineages of the 10- and the 17-offspring parents.
Fig. 3: The relationship between germline and somatic mosaicism.
Fig. 4: Summary of the ssDNMs.
Fig. 5: Germline mosaicism in the context of clinical genetics.

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Data availability

Access to these data is controlled, the DNMs are a subset of the sequence variants deposited to the European Nucleotide Archive (PRJEB15197).

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Acknowledgements

We thank all of the participants in this study. The study was performed in collaboration with Illumina.

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Authors and Affiliations

Authors

Contributions

H.J., G.A.A., F.Z., B.K., K.E.H., B.Ö.J. and D.F.G. analyzed the data. H.J., G.P., H.P.E., S.K., F.Z., B.K., A.G. and D.F.G. conceived methods for analyzing data. Ad.J., As.J. and O.Th.M. performed experiments. P.S., G.A.A., B.Ö.J., I.J., S.E.M. and S.A.G. collected samples and information. H.J., P.S., O.Th.M., U.T., G.M., B.V.H., D.F.G. and K.S. designed the study. H.J., P.S., D.F.G. and K.S. wrote the manuscript with input from G.A.A., G.P., K.E.H., S.N.S., U.T., A.K., B.V.H. and A.H.

Corresponding authors

Correspondence to Daniel F. Gudbjartsson or Kari Stefansson.

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Competing interests

All of the authors except S.E.M. are employees of deCODE Genetics/Amgen, Inc.

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Integrated supplementary information

Supplementary Figure 1 Germ cell lineages of parents with nine offspring.

a,b, The male and female germ cell lineages of a nine-offspring family. c,d, The paternal and maternal germ cell lineages of a nine-offspring family. Purple and green text correspond to DNMs determined by the trio and sibling approach, respectively. Percentages are paternal and maternal imbalances, respectively. The paternal imbalance serves as a background rate for the maternal DNMs, and vice versa. In addition to ssDNMs, we incorporated DNMs that are somatic mosaic in the parent (≥4 reads supporting the alternative allele in the parent). DNM sites are ordered according to carrier frequency, from high (top) to low (bottom) frequency.

Supplementary Figure 2 Germ cell lineages of nine-offspring parents.

a,b, The male and female germ cell lineages of a nine-offspring family. c,d, The paternal and maternal germ cell lineages of a nine-offspring family. Purple and green text correspond to DNMs determined by the trio and sibling approach, respectively. Percentages are paternal and maternal allelic imbalances, respectively. The paternal allelic imbalance serves as a background rate for the maternal DNMs, and vice versa. In addition to ssDNMs, we incorporated DNMs that are somatic mosaic in the parent (≥4 reads supporting the alternative allele in the parent). DNM sites are ordered according to carrier frequency, from high (top) to low (bottom) frequency.

Supplementary Figure 3 ssDNM rate against allelic imbalance in parents for various subsets.

a, Restricting to DNMs determined by the trio approach and DNMs from the sibling approach in which the allelic balance difference between carriers and parents was rejected. A two-sided Fisher test was used for the allelic balance test difference. The P values were adjusted with Holm multiple-testing correction using the number of DNMs found solely by the sibling approach. b, In addition to rejecting the null hypothesis as in a, we required DNMs determined by the sibling approach to have at least two siblings who were non-carriers despite having the same haplotype background as the DNM carriers (absent). For a and b, the analysis was restricted to deep-sequenced parents (13 parent pairs and 518 sibling pairs). c, Same as in a except that all sibling pairs were used (238 parent pairs and 518 sibling pairs). d, Same as in b except that all sibling pairs were used (238 parent pairs and 518 sibling pairs). The center values are means and error bars are 95% CIs.

Supplementary Figure 4 The power of the sibling method.

The power of detecting a DNM segregating in the parental germline conditional on DNM transmission.

Supplementary Figure 5 Targeted resequencing of DNM sites from the 10- and 17-sibling families.

a, The allelic imbalance from targeted resequencing against carrier status determined from whole-genome sequencing. In a, sites with over 100× coverage were used, resulting in 657 genotypes from 27 offspring from two parent pairs. In a, the hinges are the first and third quantiles, and notches are ±1.58 × IQR/√n, where IQR is the interquartile range and n is the number in each category. be, Targeted resequenced imbalance of the parents against the imbalance from whole-genome sequencing.

Supplementary Figure 6 A schematic overview of the recurrence calculator.

The green and orange states represent the intermediate analysis steps and datasets, respectively.

Supplementary Figure 7 SMPP as a function of reads supporting the alternative allele.

The vertical error bars are the 95% CIs assessed by the jackknife procedure. The center values are the means. 13 parent pairs and 1,517 sibling trios were used in the 200× subset, and 54 parent pairs and 241 sibling trios were used in the 30× subset.

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Supplementary Figures 1–7, Supplementary Tables 1–5 and Supplementary Note

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Jónsson, H., Sulem, P., Arnadottir, G.A. et al. Multiple transmissions of de novo mutations in families. Nat Genet 50, 1674–1680 (2018). https://doi.org/10.1038/s41588-018-0259-9

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