Garcia-Salinas OI et al., The American Journal of Human Genetics - Garcia-Salinas et al. develop a bioinformatic pipeline to recover early parental postzygotic mutations (PZMs) from standard-depth (~30×) trio WGS and apply it to 12,015 rare-disease trios, producing a catalog of 1,015 high-confidence autosomal parental PZMs and assessing their genomic features and clinical relevance. Key terms: parental mosaicism, postzygotic mutations, trio WGS, mutational spectrum, clinical genetics.
Study Highlights:
The authors screened unfiltered candidate de novo sites across 12,015 trios and identified 1,015 high-confidence early autosomal parental PZMs with a monomodal blood VAF distribution centered around ~5%. PZMs showed no parental age or sex bias and a distinct substitution spectrum relative to germline DNMs, with enrichment for C>A and T>A and depletion of T>C. Mutational-signature analysis attributed most variants to clock-like signatures SBS1 and SBS5 in similar proportions for PZMs and DNMs. The study recovered clinically relevant missed variants, including likely reportable events in WT1 and DYNC1H1, illustrating diagnostic and recurrence-risk implications.
Conclusion:
A lightweight annotation applied to standard clinical trio WGS can recover early parental mosaic variants at scale, revealing distinct spectral and genomic patterns and identifying clinically actionable variants that routine pipelines often miss, though detection is constrained to an intermediate VAF window by standard-depth sequencing.
Music:
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Article title:
Landscape of parental postzygotic mutations across >11,000 rare disease trios
First author:
Garcia-Salinas OI
Journal:
The American Journal of Human Genetics
DOI:
10.1016/j.ajhg.2026.06.015
Reference:
Garcia-Salinas OI, Andrews KA, Sanghvi R, et al. Landscape of parental postzygotic mutations across >11,000 rare disease trios. The American Journal of Human Genetics. 2026;113:1–9. https://doi.org/10.1016/j.ajhg.2026.06.015
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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Episode link: https://basebybase.com/episodes/hidden-mosaic-parental-pzms-417
QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-18.
QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing (a) the concept of parental postzygotic mutations (PZMs) and their discovery from standard-depth trio WGS, (b) VAF distributions and timing, (c) mutational spectra and clock-like signatures SBS1/SBS5, (d) GC-content distribution, (e) clinical implications including WT1 and DYN
- transcript topics: Definition and origin of parental postzygotic mutations (PZMs) and mosaicism; Limitations of standard diagnostic pipelines and 30× trio WGS; Bioinformatic pipeline to recover PZMs from DNM candidates; Variant allele fraction (VAF) distribution and timing (approx. third cell division); Mutational spectra and clock-like signatures SBS1/SBS5 in PZMs vs DNMs; GC-content associations and...
