Reanalysis of genomic data doubles the diagnostic yield for Welsh patients recruited to the UK 100,000 Genomes Project.

The Wales Genomic Medicine Centre recruited 438 individuals from 154 families, undiagnosed despite pre-genomic testing, into the 100,000 Genomes Project; 64% of probands had a neurological or neurodevelopmental phenotype. Initial diagnostic yield was 20.8% (32/154), with variants of uncertain significance reported in 11 further families, and 83.7% (36/43) of initial findings could have been detected by clinical exome sequencing, then the local standard of care. Reanalysis with updated prioritisation tools, expanded gene lists, re-phenotyping and segregation studies raised the yield to 42.2% (65/154), a 103% improvement. RNA analysis clarified the clinical significance of variants of uncertain significance in COQ4, ENPP1, GATAD2B, NCAPD2 and THOC2.

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

Doubling the yield through reanalysis, without new sequencing, is the most concrete argument for planned periodic reanalysis rather than on-demand. That more than 80% of initial findings were within reach of exome sequencing tempers the specific contribution of the genome in this cohort. RNA analysis to resolve variants of uncertain significance deserves a place in the reanalysis pathway.

Analysis by Dr Thibaut Benquey