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

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 (3.5-20.4per 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.

A systematic literature review of the disease burden in patients with recessive dystrophic epidermolysis bullosa

“…Second, as there are likely RDEB patients with milder phenotypes who have been misdiagnosed [ 3 ] or were underreported, these milder RDEB presentations are likely underrepresented in the literature. Thus, it is likely that severe and systemic manifestations such as non-esophageal strictures and stenoses, pseudosyndactyly, and microstomia, are overreported.…”

“…However, a more recent genotypic modeling of publicly available whole-exome and whole-genome sequencing estimated an incidence of 95 cases per one million births. This suggests that the National EB Registry estimates may be significantly understated, potentially due to underestimation of less severe cases of RDEB, likely mis-diagnosed as EB Simplex or de novo variants of Dominant Dystrophic EB (DDEB) [ 3 ]. This underestimation may also result in overestimation of systemic and severe manifestations.…”

Epidemiological, clinical, pathological and genetic characteristics of epidermolysis bullosa in New Zealand

“…However, even these rates are likely to be an underestimate, perhaps by orders of magnitude, as suggested by computer-based modelling of recessive DEB incidence rates (based on carrier frequencies and in silico prediction tools). 16 In addition, as we did not have ethical approval to approach the families of deceased individuals, these data do not include infants with the most severe life-limiting forms of EB (mainly severe JEB).…”

Genetic epidemiology approach to estimating birth incidence and current disease prevalence for rhizomelic chondrodysplasia punctata

“…However, since the advent of large-scale genomics studies of general populations, more accurate estimates can be calculated for recessive disorders, using minor allelic frequencies for disease-causing mutations where numerous unaffected carriers are detected [ 16 , 17 ]. These approaches have already been applied to estimate the disease burden in other rare diseases such as epidermolysis bullosa [ 18 ] and autosomal recessive inherited retinal diseases [ 19 ].…”