Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data.
Child
Cohort Studies
Developmental Disabilities
/ diagnosis
Exome
/ genetics
Female
Genetic Testing
/ methods
Genetic Variation
Haplotypes
/ genetics
High-Throughput Nucleotide Sequencing
Humans
Male
Maternal Inheritance
/ genetics
Mosaicism
Parents
Paternal Inheritance
/ genetics
Exome Sequencing
/ methods
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 07 2019
05 07 2019
Historique:
received:
24
01
2019
accepted:
12
06
2019
entrez:
7
7
2019
pubmed:
7
7
2019
medline:
23
10
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31278258
doi: 10.1038/s41467-019-11059-2
pii: 10.1038/s41467-019-11059-2
pmc: PMC6611863
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2985Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/3
Pays : United Kingdom
Organisme : Wellcome Trust (Wellcome)
ID : WT098051
Pays : International
Commentaires et corrections
Type : ErratumIn
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