Browse by author
Lookup NU author(s): Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Authors.Early postzygotic mutations (PZMs) that arise after fertilization but prior to primordial germ cell specification may be present in both somatic and germ cells, causing mosaicism in a parent and constitutive inheritance in their offspring. In clinical family-trio whole-genome sequencing (WGS), such variants are systematically missed because their sub-heterozygous variant allele fraction (VAF) prevents heterozygous calling in the parent, while residual parental allele support disqualifies the variant as a candidate germline de novo mutation (DNM) in the child. Here, we developed a bioinformatic approach to ascertain parental PZMs from unfiltered DNM candidates in standard-depth (∼30×) trio WGS and applied it to 12,015 trios from the Genomics England 100,000 Genomes Project. We identified 1,015 high-confidence early autosomal parental PZMs, a large single-source catalog of this mutation class. These exhibited a monomodal VAF distribution centered around 5% in parental blood, consistent with empirically characterized ascertainment boundaries imposed by standard-depth sequencing and germline variant calling. PZMs showed no parental age or sex bias and displayed a mutational spectrum distinct from that of DNMs, with enrichment for C>A and T>A substitutions and depletion of T>C. Mutational signature analysis revealed that both mutation types are shaped by clock-like signatures SBS1 and SBS5 in similar proportions, suggesting that spectral differences reflect shifts within shared mutagenic processes. Exploratory genomic distribution analysis revealed a negative PZM association with GC content, in contrast to the positive association for DNMs. Among these, we found variants in DYNC1H1 and WT1 with potential clinical relevance that were missed by routine diagnostic pipelines.
Author(s): Garcia-Salinas OI, Andrews KA, Sanghvi R, Sayer JA, Torra I Benach M, Pham MH, Scally A, Martin HC, Rahbari R
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2026
Pages: epub ahead of print
Online publication date: 13/07/2026
Acceptance date: 23/06/2026
Date deposited: 27/07/2026
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2026.06.015
DOI: 10.1016/j.ajhg.2026.06.015
Data Access Statement: There are restrictions on the availability of the catalog of PZMs described in this manuscript due to GEL policies on the export of individual-level information. This catalog can be accessed from the GEL research environment upon request to join the GEL research network at https://www.genomicsengland.co.uk/join-us/academics. In the GEL research environment, our catalog of PZMs and its associated code can be found in the following path: /re_gecip/shared_allGeCIPs/parental_pzm_cat.
Altmetrics provided by Altmetric
