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. 2019 Dec 24:12:933-942.
doi: 10.2147/CCID.S232547. eCollection 2019.

From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Shaundra Eichstadt  1 , Jean Y Tang  1 , Daniel C Solis  1 , Zurab Siprashvili  1 , M Peter Marinkovich  1   2 , Nedra Whitehead  3 , Matthew Schu  3 , Fang Fang  3 , Stephen W Erickson  3 , Mary E Ritchey  3 , Max Colao  4 , Kaye Spratt  4 , Amir Shaygan  5 , Mark J Ahn  5 , Kavita Y Sarin  1
Affiliations

From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Shaundra Eichstadt et al. Clin Cosmet Investig Dermatol. .

Erratum in

Abstract

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited genetic disorder characterized by recurrent and chronic open wounds with significant morbidity, impaired quality of life, and early mortality. RDEB patients demonstrate reduction or structural alteration type VII collagen (C7) owing to mutations in the gene COL7A1, the main component of anchoring fibrils (AF) necessary to maintain epidermal-dermal cohesion. While over 700 alterations in COL7A1 have been reported to cause dystrophic epidermolysis bullosa (DEB), which may be inherited in an autosomal dominant (DDEB) or autosomal recessive pattern (RDEB), the incidence and prevalence of RDEB is not well defined. To date, the widely estimated incidence (0.2-6.65 per million births) and prevalence (3.5-20.4 per million people) of RDEB has been primarily characterized by limited analyses of clinical databases or registries.

Methods: Using a genetic modelling approach, we use whole exome and genome sequencing data to estimate the allele frequency of pathogenic variants. Through the ClinVar and NCBI database of human genome variants and phenotypes, DEB Register, and analyzing premature COL7A1 termination variants we built a model to predict the pathogenicity of previously unclassified variants. We applied the model to publicly available sequences from the Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD) and identified variants which were classified as pathogenic for RDEB from which we estimate disease incidence and prevalence.

Results: Genetic modelling applied to the whole exome and genome sequencing data resulted in the identification of predicted RDEB pathogenic alleles, from which our estimate of the incidence of RDEB is 95 per million live births, 30 times the 3.05 per million live birth incidence estimated by the National Epidermolysis Bullosa Registry (NEBR). Using a simulation approach, we estimate a mean of approximately 3,850 patients in the US who may benefit from COL7A1-mediated treatments in the US.

Conclusion: We conclude that genetic allele frequency estimation may enhance the underdiagnosis of rare genetic diseases generally, and RDEB specifically, which may improve incidence and prevalence estimates of patients who may benefit from treatment.

Keywords: Dystrophic Epidermolysis Bullosa; genotype; incidence; phenotype; prevalence.

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Conflict of interest statement

Dr Shaundra Eichstadt reports grants from Epidermolysis Bullosa Research Partnershipand Epidermolysis Bullosa Medical Research Foundation during the conduct of the study. Dr Zurab Siprashvili reports a patent: Gene Therapy for Recessive Dystrophic Epidermolysis Bullosa using Genetically Corrected Autologous Keratinocytes, licensed to Abeona Therapeutics. Dr Mary Beth Ritchey reports contracted work for assessment of the incidence of RDEB for Abeona Therapeutics during the conduct of the study. Mr Max Colao reports he is employed by Abeona Therapeutics. The authors declare that they have no other competing interests.

Figures

Figure 1
Figure 1
Model Classification of Training Data. The 3D scatter plot shown here demonstrates the ability of the classifier and three components to stratify the variants into similar functional clusters.
Figure 2
Figure 2
Distribution of Pathogenicity Scores in Training Data.
Figure 3
Figure 3
Distribution of Allele Frequencies.
See this image and copyright information in PMC

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