Exome sequencing pilot study in children with carbamazepine‐induced serious skin reactions

Abstract

Stevens-Johnson syndrome (SJS) and drug-induced hypersensitivity syndrome (HSS) are life-threatening drug hypersensitivity reactions. Previous studies on genetic predictors for SJS and HSS were focused on immune-related genes and on known, frequent polymorphisms in the genome. For the anticonvulsant carbamazepine (CBZ), genetic markers for SJS and HSS have been identified in the HLA region (HLA-B*15:02, HLA-A*31:01). However, many patients carrying HLA-B*15:02 or HLA-A*31:01 tolerate CBZ, resulting in a low positive predictive value of a genetic test for these markers alone. In this pilot study, we aimed to identify novel genetic variants potentially associated with CBZ-induced SJS and HSS using whole exome sequencing in seven Canadian children with CBZ-SJS and five children with CBZ-HSS. A DNA pool from 95 CBZ-tolerant children was sequenced to estimate variant frequencies for comparison with hypersensitivity cases. All study participants were recruited through the Canadian Pharmacogenomics Network for Drug Safety. No individual rare single nucleotide variant (SNV) was observed in all SJS or HSS cases, respectively. Single variant and gene-based analyses revealed several candidate genes and variants overrepresented in hypersensitivity patients, including immune regulatory and cell adhesion genes. More candidates were identified when analyzing SJS and HSS separately, suggesting different underlying mechanisms of these hypersensitivity reactions. With a hypothesis-free, comprehensive genetic screening approach, we identified new candidate genes and variants, which require follow-up in additional patients to further investigate their potential involvement in the development of CBZ-induced SJS or HSS.