Pediatric pharmacogenomics from whole-exome sequencing: developmentally appropriate interpretation in 1,159 Russian children and newborns

The activity of drug-metabolizing enzymes and transporters changes with age: the same genotype therefore does not predict the same phenotype in a newborn and in an adult, something current interpretation algorithms do not incorporate.

The authors analysed whole-exome sequencing data from 524 paediatric patients and 635 newborns, keeping only pharmacogenomic annotations of PharmGKB/ClinPGx evidence level 1A-2B carrying the 'Pediatrics' tag. Clinically relevant annotations — drug avoidance or dose modification — accounted for only 5% of all annotations in both cohorts, and 67.6% (paediatric cohort) and 67.2% (neonatal cohort) of these involved alleles with altered function. In newborns, genotype-based recommendations were concordant with the ontogenetic status of the metabolizing enzyme in only 5 of 14 gene-drug pairs (35.71%). Among 100 paediatric patients whose records were reviewed, 21% had experienced an adverse drug reaction, but only two cases could be explained by high-evidence annotations; ranking 27 gene-variant-drug-reaction associations by relative population burden placed irinotecan-induced neutropenia in UGT1A1 28 carriers and carbamazepine-induced severe cutaneous reactions in HLA-A 31:01 carriers at the top.

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

The number to remember is the discordance: in newborns, for two thirds of the gene-drug pairs examined, the genotype-derived recommendation did not match the actual maturity of the enzyme involved. Handing a newborn a pharmacogenomic report calibrated on adults therefore yields information that is at best useless. The proposed model — mandatory reporting of age, ontogenetic adjustment, evidence-level stratification — is common sense, but it remains a preprint without prospective validation, and the 21% of adverse reactions observed almost never had a pharmacogenomic explanation.

Analysis by Dr Thibaut Benquey