Landscape of parental postzygotic mutations across >11,000 rare disease trios.

Early parental postzygotic mutations with low allele fraction, constitutively transmitted

Early parental postzygotic mutations (PZMs), arising after fertilization, are systematically missed in trio sequencing because their sub-heterozygous allele fraction prevents parental calling while disqualifying the variant as a de novo in the child. The authors developed a bioinformatic approach applied to 12,015 trios from the 100,000 Genomes Project and identified 1,015 high-confidence early autosomal PZMs. These show a median allele fraction around 5% in parental blood, no age or sex bias, and a mutational spectrum distinct from de novo mutations. Clinically relevant DYNC1H1 and WT1 variants missed by routine pipelines were recovered.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A methodologically rigorous study addressing a blind spot of trio WGS: parental PZMs have direct implications for genetic counseling (recurrence risk) and diagnostic yield. The recovery of clinically relevant variants (DYNC1H1, WT1) argues for integrating this analysis into pipelines. The value lies in fully exploiting already-generated data.

Analysis by Dr Thibaut Benquey