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. 2021 Mar 1:14:287-299.
doi: 10.2147/PGPM.S289869. eCollection 2021.

Whole-Exome Sequencing in Patients Affected by Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Reveals New Variants Potentially Contributing to the Phenotype

Dora Janeth Fonseca #  1 , Adrien Morel #  1 , Kevin Llinás-Caballero  1 , David Bolívar-Salazar  1 , Paul Laissue  1   2
Affiliations

Whole-Exome Sequencing in Patients Affected by Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Reveals New Variants Potentially Contributing to the Phenotype

Dora Janeth Fonseca et al. Pharmgenomics Pers Med. .

Abstract

Background: Adverse drug reactions (ADRs) are frequent occurring events that can essentially be defined as harmful or unpleasant symptoms secondary to the use of a medicinal product. ADRs involve a wide spectrum of clinical manifestations ranging from minor itching and rash to life-threatening reactions. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare ADRs. SJS-TEN may be considered a polygenic pathology due to additive/epistatic effects caused by sequence variants in numerous genes. Next-generation sequencing (NGS) represents a potentially interesting exploration tool in such scenario as it facilitates the simultaneous analysis of large genomic regions and genes at affordable cost.

Methods: The present study has involved using whole-exome sequencing (WES) for the first time on SJS-TEN patients. It involved robust and innovative multistep bioinformatics analysis focusing on 313 candidate genes potentially participating in the disease's aetiology, specific drugs' metabolism and gene regulation.

Results: We identified combinations of frequently occurring and rare variants that may contribute to the disease's pathogenesis. Depending on the specific drug being taken, different variants (and alleles) in NAT2, CYP2D8, CYP2B6, ABCC2, UGT2B7 and TCF3 were identified as coherent candidates representing potential future markers for SJS-TEN.

Conclusion: The present study proposed and has described (for the first time) a large-scale genomic analysis of patients affected by SJS-TEN. The genes and variants identified represent relevant candidates potentially participating in the disease's pathogenesis. Corroborating that proposed by others, we found that complex combinations of frequently occurring and rare variants participating in particular drug metabolism molecular cascades could be associated with the phenotype. TCF3 TF may be considered a coherent candidate for SJS-TEN that should be analysed in new cohorts of patients having ADRs.

Keywords: Stevens-Johnson syndrome; molecular aetiology; toxic epidermal necrolysis; whole-exome sequencing.

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Conflict of interest statement

PL declares that his present salary is paid by BIOPAS Laboratories for working in projects different to that described in the present manuscript. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Methodological scheme for filtering genomic variants in SJS-TEN patients.
Figure 2
Figure 2
Distribution of genomic variants, filtered from specific subsets, found in SJS-TEN patients.
See this image and copyright information in PMC

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References

    1. Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf. 2005;28(10):851–870. doi:10.2165/00002018-200528100-00003 - DOI - PubMed
    1. Yip VL, Alfirevic A, Pirmohamed M. Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review. Clin Rev Allergy Immunol. 2015;48(2–3):165–175. doi:10.1007/s12016-014-8418-y - DOI - PubMed
    1. Duong TA, Valeyrie-Allanore L, Wolkenstein P, Chosidow O. Severe cutaneous adverse reactions to drugs. Lancet. 2017;390(10106):1996–2011. doi:10.1016/s0140-6736(16)30378-6 - DOI - PubMed
    1. Abe R. Immunological response in Stevens-Johnson syndrome and toxic epidermal necrolysis. J Dermatol. 2015;42(1):42–48. doi:10.1111/1346-8138.12674 - DOI - PubMed
    1. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486. doi:10.1038/428486a - DOI - PubMed

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