Multigene Next-Generation Sequencing Panel Identifies Pathogenic Variants in Patients with Unknown Subtype of Epidermolysis Bullosa: Subclassification with Prognostic Implications

Vahidnezhad, Hassan; Youssefian, Leila; Saeidian, Amir Hossein; Touati, Andrew; Sotoudeh, Soheila; Abiri, Maryam; Barzegar, Mohammadreza; Aghazadeh, Nessa; Mahmoudi, Hamidreza; Norouz‐zadeh, Sara; Hamid, Mohammad; Zahabiyon, Mahla; Bagherian, Hamideh; Zeinali, Sirous; Fortina, Paolo; Uitto, Jouni

doi:10.1016/j.jid.2017.07.830

Cited by 32 publications

(31 citation statements)

References 13 publications

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“…We identified the disease‐causing variants and consequently predicted the EB type of 82 from the 87 patients, resulting in an efficiency of 94.3%. Vahidnezhad et al developed a multigene panel including 21 genes and found an efficiency of 83.5% predicting the subtype of EB in 76 out of 91 families . Has et al elucidated 90% (36 of 40) of the studied cases by a NGS‐panel that included 49 genes .…”

Section: Discussionmentioning

confidence: 99%

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An overview of the genetic basis of epidermolysis bullosa in Brazil: discovery of novel and recurrent disease‐causing variants

et al. 2019

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Epidermolysis bullosa (EB) is a genodermatosis that encompasses a group of clinically and genetically heterogeneous disorders classified in four major types: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler syndrome. Our aim was to characterize recurrent and novel mutations associated to EB in a sample of Brazilian patients. Eighty‐seven patients (25 EBS, 4 JEB and 58 DEB) were studied. We performed a next‐generation sequencing‐based multigene panel through ion torrent technology including 11 genes: KRT5, KRT14, PLEC, TGM5, LAMA3, LAMB3, LAMC2, COL17A1, ITGB4, COL7A1, and FERMT1. A total of 72 different pathogenic or likely pathogenic variants were identified, 32 of them are novel. The causal variant was detected in 82 patients (efficiency of 94.3%). Pathogenic variants in the residue 125 of KRT14 were identified in 32% of all EBS patients. In DEB patients, four COL7A1 variants were quite frequent, some of them clustered in specific Brazilian regions. Our study extends the spectrum of known mutations in EB and describes, for the first time, the genetic profile of EB patients from Brazil.

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Section: Discussionmentioning

confidence: 99%

“…Vahidnezhad et al developed a multigene panel including 21 genes and found an efficiency of 83.5% predicting the subtype of EB in 76 out of 91 families. 39 identified in two EBS-generalized patients ( Figure S1). Homozygous pathogenic variants in KRT5 and KRT14 were also associated with EBS-generalized in two patients.…”

Section: Discussionmentioning

confidence: 99%

An overview of the genetic basis of epidermolysis bullosa in Brazil: discovery of novel and recurrent disease‐causing variants

et al. 2019

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“…The phenotypic heterogeneity of different forms of EB reflects the fact that as many as 20 different genes encoding the components of the dermal–epidermal attachment complexes harbor mutations in different subtypes of EB (Uitto et al, ). Recently, a number of NGS approaches have been adopted, including gene‐targeted panels, as well as whole exome sequencing and whole genome sequencing (WGS) for study of EB (Takeichi et al., ; Vahidnezhad, Youssefian, Saeidian, et al., ; Vahidnezhad, Youssefian, Zeinali, et al., ). We have developed a NGS panel which consists of 21 genes associated with different skin fragility syndromes, including 19 genes shown to harbor mutations in patients with EB.…”

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“…We have developed a NGS panel which consists of 21 genes associated with different skin fragility syndromes, including 19 genes shown to harbor mutations in patients with EB. Sequencing of a large number of EB patients, primarily from consanguineous marriages in Iran, identified a number of novel, previously unreported mutations in a number of cases with unusual genetic constellations and complex cutaneous phenotypes not diagnostic of any of the particular subtype of EB (Vahidnezhad, Youssefian, Saeidian, et al., ). In this study, we report identification of homozygous mutations in two distinct genes associated with different subtypes of EB resulting in an unusual cutaneous phenotype (Figure a).…”

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Next generation sequencing identifies double homozygous mutations in two distinct genes (EXPH5 and COL17A1 ) in a patient with concomitant simplex and junctional epidermolysis bullosa

et al. 2018

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Epidermolysis bullosa (EB) is a heterogeneous group of heritable blistering diseases. We developed a next generation sequencing (NGS) panel covering 21 genes associated with skin fragility disorders, and it was applied to DNA from 91 probands with the diagnosis of EB. In one patient, novel homozygous mutations were disclosed in two different, unlinked EB-associated genes: EXPH5, chr11 g.108510085G > A; p.Arg1808Ter and COL17A1, chr10 g.104077423delT; p.Thr68LeufsTer106. Consequences of the COL17A1 mutation were examined by RNAseq which revealed a complex splicing pattern predicting synthesis of a truncated polypeptide (85%) or in-frame deletion of exon 4 (15% of transcripts). Transmission electron microscopy (TEM) and immunostaining revealed findings consistent with EB simplex (EBS) and junctional EB (JEB), and clinical examination revealed a complex phenotype with features of both subtypes. This case illustrates the power of next generation sequencing in identifying mutations in patients with complex EB phenotype, with implications for genotype-phenotype correlations, prenatal testing, and genetic counseling of families at risk for recurrence.

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Mutation update: The spectra of PLEC sequence variants and related plectinopathies

et al. 2022

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Plectin, encoded by PLEC, is a cytoskeletal linker of intermediate filaments expressed in many cell types. Plectin consists of three main domains that determine its functionality: the N-terminal domain, the Rod domain, and the C-terminal domain.Molecular defects of PLEC correlating with the functional aspects lead to a group of rare heritable disorders, plectinopathies. These multisystem disorders include an autosomal dominant form of epidermolysis bullosa simplex (EBS-Ogna), limb-girdle muscular dystrophy (LGMD), aplasia cutis congenita (ACC), and an autosomal recessive form of EBS, which may associate with muscular dystrophy (EBS-MD), pyloric atresia (EBS-PA), and/or congenital myasthenic syndrome (EBS-MyS). In this study, genotyping of over 600 Iranian patients with epidermolysis bullosa by nextgeneration sequencing identified 15 patients with disease-causing PLEC variants. This mutation update analyzes the clinical spectrum of PLEC in our cohort and in the literature and demonstrates the relationship between PLEC genotype and phenotypic manifestations. This study has integrated our seven novel PLEC variants and phenotypic findings with previously published data totaling 116 variants to provide the most complete overview of pathogenic PLEC variants and related disorders.

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Multigene Next-Generation Sequencing Panel Identifies Pathogenic Variants in Patients with Unknown Subtype of Epidermolysis Bullosa: Subclassification with Prognostic Implications

Cited by 32 publications

References 13 publications

An overview of the genetic basis of epidermolysis bullosa in Brazil: discovery of novel and recurrent disease‐causing variants

An overview of the genetic basis of epidermolysis bullosa in Brazil: discovery of novel and recurrent disease‐causing variants

Next generation sequencing identifies double homozygous mutations in two distinct genes (EXPH5 and COL17A1 ) in a patient with concomitant simplex and junctional epidermolysis bullosa

Mutation update: The spectra of PLEC sequence variants and related plectinopathies

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