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Nat Commun. 2019 Jul 5;10(1):2985. doi: 10.1038/s41467-019-11059-2.

Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data.

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Institute of Biomedicine and Clinical Science, College of Medicine and Health, University of Exeter, RILD Building, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, CB10 1SD, UK.
MRC Human Genetics Unit, University of Edinburgh, Edinburgh, EH4 2XU, UK.
Clinical Genetics, Box 134 Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK.


Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants.

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