Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation

By informing timely targeted treatments, rapid whole-genome sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric intensive care units(ICUs). The need for highly qualified professionals to decipher results, however, precludes widespread implementation. We describe a platform for population-scale, provisional diagnosis of genetic diseases with automated phenotypingand interpretation. Genome sequencing was expedited by bead-based genome librarypreparation directly from blood samples and sequencing of paired 100-nt reads in 15.5 hours. Clinical natural language processing (CNLP) automatically extracted children’s deep phenomesfrom electronic health records with 80% precision and 93% recall. In 101 children with 105 genetic diseases, a mean of 4.3 CNLP-extracted phenotypicfeatures matched the expected phenotypicfeatures of those diseases, compared with a match of 0.9 phenotypicfeatures used in manual interpretation. We automated provisional diagnosis by combining the ranking of the similarity of a patient’s CNLP phenomewith respect to the expected phenotypicfeatures of all genetic diseases, together with the ranking of the pathogenicity of all of the patient’s genomic variants. Automated, retrospective diagnoses concurred well with expert manual interpretation (97% recall and 99% precision in 95 children with 97 genetic diseases). Prospectively, our platform correctly diagnosed three of seven seriously ill ICU infants (100% precisionand recall) with a mean time saving of 22:19 hours. In each case, the diagnosis affected treatment. Genome sequencing with automated phenotypingand interpretation in a median of 20:10 hours may increase adoption in ICUs and, thereby, timely implementation of precise treatments.