Gene panel for the diagnosis of epidermolysis bullosa: proposal for a viable and efficient approach<sup>,</sup>

Mariath, Luiza Monteavaro; Kiszewski, Ana Elisa; Frantz, Jeanine Aparecida; Siebert, Marina; Matte, Ursula; Schuler-Faccini, Lavínia

doi:10.1016/j.abd.2020.05.015

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Original Article • An. Bras. Dermatol. 96 (2) • Mar-Apr 2021 • https://doi.org/10.1016/j.abd.2020.05.015 copy

Gene panel for the diagnosis of epidermolysis bullosa: proposal for a viable and efficient approach^☆ ☆ How to cite this article: Mariath LM, Kiszewski AE, Frantz JA, Siebert M, Matte U, Schuler-Faccini L. Gene panel for the diagnosis of epidermolysis bullosa: proposal for a viable and efficient approach. An Bras Dermatol. 2021;96:155-62. ^,^☆☆ ☆☆ Study conducted at Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background:

Epidermolysis bullosa is characterized by cutaneous fragility and blistering. Historically, diagnosis is achieved by immunofluorescence mapping or transmission electron microscopy, both involving biopsy procedures. Genetic analysis, especially through next-generation sequencing, is an important tool for the diagnosis of this disease. In Brazil, access to diagnostic methods is limited, and consequently, most patients do not have an accurate diagnosis. Diagnosis allows the indication of prognosis and genetic counselling of the patient.

Objectives:

To evaluate the cost-effectiveness of a gene panel compared to immunofluorescence mapping and transmission electron microscopy by analyzing its benefits, limitations, and economic aspects.

Methods:

The gene panel included the 11 main genes associated with epidermolysis bullosa. The techniques were compared, assessing the average cost, advantages, and limitations, through a price survey and literature review.

Results:

Both immunofluorescence mapping and transmission electron microscopy require skin biopsy, are dependent on the investigator's expertise, and are subject to frequent inconclusive results. The gene panel is effective for the conclusive diagnosis of epidermolysis bullosa, presents high efficiency and accuracy, is economically feasible, and excludes the need for biopsy. The gene panel allows for prognosis, prenatal genetic diagnosis, and genetic counseling.

Study limitations:

It was not possible to find laboratories that perform transmission electron microscopy for epidermolysis bullosa diagnosis in Brazil.

Conclusion:

This study supports the gene panel as the first-choice method for epidermolysis bullosa diagnosis.

KEYWORDS
Genetic counseling; Diagnosis; Epidermolysis bullosa; Genetic testing

	Immunofluorescence mapping	Transmission electronic microscopy	Gene panel by NGS
Number of laboratories	Main type of EB and the likely altered protein	Analysis of specific structures of EB subtypes	Identification of the genetic alteration
	Diagnostic accuracy	Diagnostic accuracy	Determination of EB type and inheritance pattern
	Fast execution		Determination of EB type and inheritance pattern
	Prognostic value		No biopsy needed
			No biopsy needed
			High efficiency (94.3%)^c c Efficiency identified in a study with the proposed gene panel.13
			Diagnostic accuracy^d d It is important to note the difference between "efficiency" and "accuracy." Efficiency refers to the proportion of solved cases (that is, cases with the identified pathogenic mutation) in relation to the total number of patients analyzed. The term "accuracy", in turn, refers to the precision (correctness) of the results.
			Informative and conclusive for most cases
			Enables prenatal and pre-implantation genetic diagnosis
			Sample transportation easiness
Disadvantages	Biopsy	Biopsy	High price
	Dependent on the researcher's experience	High price	Expert analysis centers needed
	It is not possible to accurately distinguish all subtypes of EB	Few centers specialized in the technique	Experience required for interpretation and classification of variants
	Inconclusive results are common	Expertise required for correct analysis
	Possible technical artifacts	Possible technical artifacts
	No information on genetic alteration
Cost per patient ^a a Costs are based on the mean estimate of prices surveyed in the market.	R$ 500.00	Not performed in Brazil^b b To the best of the authors' knowledge, according to the research conducted in this study. (in the United States: US$ 980.00)	R$ 800.00

Clinical case

A 32-year-old patient was diagnosed late with epidermolysis bullosa (at the age of 15 years) due to the mild clinical presentation. The patient's symptoms were subtle when compared with more severe cases of EB. Blisters were distributed in the pre-tibial region and only a slight presence of blisters was found in the hands. Nail dystrophy was observed only on toenails.
The patient underwent a skin biopsy which was inconclusive. The clinical examination carried out by expert dermatologists suggested the probable type of EB: localized EB simplex.
The genetic analysis by the gene panel was in contrast to what was expected by the clinicians: two pathogenic variants were found in the COL7A1 gene, revealing that it was a case of recessive dystrophic EB (RDEB).
The most well-known phenotype of RDEB is quite severe, involving high induction and generalized distribution of blisters and pseudosyndactyly. Mild forms of RDEB are more rare and difficult to determine by clinical examination. Studies have shown that genetic alteration has a great influence on clinical presentation. Both pathogenic variants identified in the patient act by altering the splicing of COL7A1. Other very mild cases of RDEB have already been associated with this same type of variant.
The case reported here exemplifies the importance of genetic analysis for the correct determination of the type of EB. Since the pattern of inheritance varies between types of EB (EBS: dominant, JEB: recessive, DEB: dominant or recessive), knowledge of its classification is essential for correct genetic counseling.

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E-mail: revista@sbd.org.br

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[1] * Corresponding author at: Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. E-mail: lavinia.faccini@ufrgs.br (L. Schuler-Faccini).