Landscape of parental postzygotic mutations across >11,000 rare disease trios.
Researchers identified a hidden class of genetic mutations in disease-causing genes that standard DNA testing misses, improving how doctors estimate recurrence risk in rare disease families.
Analysis of 12,015 rare disease family trios from the 100,000 Genomes Project identified 1,015 parental postzygotic mutations with variant allele fractions around 5%, representing a class of clinically relevant variants that standard WGS calling pipelines systematically miss because sub-heterozygous parental mosaicism is not captured. PZMs showed a distinct mutational spectrum from de novo mutations and included variants in disease genes (DYNC1H1, WT1) with direct clinical implications for genetic counseling and recurrence risk estimation in rare disease families.
What the study was
- Study design
- Retrospective cohort bioinformatic study of clinical WGS trios (Genomics England 100,000 Genomes Project)
- Population
- Rare disease families enrolled in Genomics England 100,000 Genomes Project (n=12,015 trios)
- Sample size
- 12015
- Category
- Genomics/Precision Medicine
- Maturity
- Validated
- Journal
- American journal of human genetics
Why it surfaced
Largest single-source catalog of parental PZMs from clinical rare disease WGS; identifies a systematically missed diagnostic category with clear clinical counseling implications; clinically relevant variants found in known disease genes warrant updating of rare disease diagnostic pipelines.
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