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

Authors Fonseca DJ, Morel A, Llinás-Caballero K, Bolívar-Salazar D, Laissue P

Received 1 November 2020

Accepted for publication 26 December 2020

Published 1 March 2021 Volume 2021:14 Pages 287—299


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Martin Bluth

Dora Janeth Fonseca,1,* Adrien Morel,1,* Kevin Llinás-Caballero,1 David Bolívar-Salazar,1 Paul Laissue1,2

1Center for Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia; 2BIOPAS Laboratoires, Orphan Diseases Unit, BIOPAS GROUP, Bogotá, Colombia

*These authors contributed equally to this work

Correspondence: Paul Laissue
BIOPAS Laboratoires, BIOPAS Group, Calle 127A #53ª-45, Bogotá, CP, 11001, Colombia
Tel +57 3212010179
Email [email protected]

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: whole-exome sequencing, Stevens-Johnson syndrome, toxic epidermal necrolysis, molecular aetiology

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