Evolution of genome diagnostics in epidermolysis bullosa: Unveiling the power of next-generation sequencing

R Baardman; H H Lemmink; V K Yenamandra; S Z Commandeur-Jan; M Viel; K A Kooi; G F H Diercks; R Meijer; M van Geel; H Scheffer; R J Sinke; B Sikkema-Raddatz; M C Bolling; P C van den Akker

doi:10.1111/jdv.19938

Evolution of genome diagnostics in epidermolysis bullosa: Unveiling the power of next-generation sequencing

J Eur Acad Dermatol Venereol. 2024 Mar 11. doi: 10.1111/jdv.19938. Online ahead of print.

Authors

R Baardman¹, H H Lemmink², V K Yenamandra³, S Z Commandeur-Jan², M Viel², K A Kooi², G F H Diercks^{1

4}, R Meijer⁵, M van Geel⁶, H Scheffer⁵, R J Sinke², B Sikkema-Raddatz², M C Bolling¹, P C van den Akker^{1

2}

Affiliations

¹ Department of Dermatology, UMCG Centers of Expertise for Blistering Diseases and Genodermatoses, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
² Department of Genetics, UMCG Centers of Expertise for Blistering Diseases and Genodermatoses, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Academy of Scientific and Innovative Research South Campus, CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi, India.
⁴ Department of Pathology, UMCG Centers of Expertise for Blistering Diseases and Genodermatoses, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁵ Department of Genetics, University Medical Center Nijmegen, University of Nijmegen, Nijmegen, The Netherlands.
⁶ Department of Genetics, Maastricht University Medical Center, University of Maastricht, Maastricht, The Netherlands.

PMID: 38465480
DOI: 10.1111/jdv.19938

Abstract

Background: Genome diagnostics is considered gold standard diagnostics for epidermolysis bullosa (EB), a phenotypically and genetically heterogeneous group of rare disorders characterized by blistering and wounding of mucocutaneous tissues. EB is caused by pathogenic variants in genes encoding proteins of the dermo-epidermal junction. Accurate genetic diagnosis of EB is crucial for prognostication, counselling and precision-medicine. Genome diagnostics for EB started in 1991 with the introduction of Sanger sequencing (SS), analysing one gene at a time. In 2013, SS was superseded by next-generation sequencing (NGS), that allow for high-throughput sequencing of multiple genes in parallel. Several studies have shown a beneficial role for NGS in EB diagnostics, but its true benefit has not been quantified.

Objectives: To determine the benefit of NGS in EB by systematically evaluating the performance of different genome diagnostics used over time based on robust data from the Dutch EB Registry.

Methods: The diagnostic performances of SS and NGS were systematically evaluated in a retrospective observational study including all index cases with a clinical diagnosis of EB in whom genome diagnostics was performed between 01 January 1994 and 01 January 2022 (n = 308), registered at the Dutch EB Expertise Centre.

Results: Over time, a genetic diagnosis was made in 289/308 (94%) EB cases. The diagnostic yield increased from 89% (SS) to 95% (NGS). Most importantly, NGS significantly reduced diagnostic turnaround time (39 days vs. 211 days, p < 0.001). The likelihood of detecting variants of uncertain significance and additional findings increased from 5% and 1% (SS) to 22% and 13% (NGS) respectively.

Conclusions: Our study quantifies the benefit of NGS-based methods and demonstrate they have had a major impact on EB diagnostics through an increased diagnostic yield and a dramatically decreased turnaround time (39 days). Although our diagnostic yield is high (95%), further improvement of genome diagnostics is urgently needed to provide a genetic diagnosis in all EB patients.

Abstract

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