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

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
• phenotype
• incidence
• prevalence

View correction statement:

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

Abbreviations

AF, anchoring fibrils; C7, type VII collagen; ExAC,Exome Aggregation Consortium; gnomAD, Genome Aggregation Database; NC1,Amino-terminal noncollagenous domain; NC2, carboxyl-terminal noncollagenous domain; PTC, premature stop codons; WES, whole-exome sequencing; WGS, whole-genome sequencing.

Data Sharing Statement

All databases referenced in the manuscript are publicly available, including ExAC (Exome Aggregation Consortium) and gnomAD (Genome Aggregation Database).

Author Contributions

All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

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.

Additional information

Funding

Supported in part by a financial contribution from Abeona Therapeutics. Dr. Marinkovich was supported by funding from the Office of Research and Development, Palo Alto VA Medical Center.