An In-Depth Single-Gene Worldwide Carrier Frequency and Genetic Prevalence Analysis of CYP4V2 as the Cause of Bietti Crystalline Dystrophy.

Conclusions: Our analysis estimates BCD prevalence and revealed large differences among various populations. Moreover, it highlights advantages and limitations of the gnomAD database. Methods: CYP4V2 gnomAD data and reported mutations were used to calculate carrier frequency of each variant. An evolutionary-based sliding window analysis was used to detect conserved protein regions. Potential exonic splicing enhancers (ESEs) were identified using ESEfinder. Purpose: Bietti crystalline dystrophy (BCD) is a rare monogenic autosomal recessive (AR) chorioretinal degenerative disease caused by biallelic mutations in CYP4V2. The aim of the current study was to perform an in-depth calculation of worldwide carrier frequency and genetic prevalence of BCD using gnomAD data and comprehensive literature CYP4V2 analysis. Results: We identified 1171 CYP4V2 variants, 156 of which were considered pathogenic, including 108 reported in patients with BCD. Carrier frequency and genetic prevalence calculations confirmed that BCD is more common in the East Asian population, with ∼19 million healthy carriers and 52,000 individuals who carry biallelic CYP4V2 mutations and are expected to be affected. Additionally, we generated BCD prevalence estimates of other populations, including African, European, Finnish, Latino, and South Asian. Worldwide, the estimated overall carrier frequency of CYP4V2 mutation is 1:210, and therefore, ∼37 million individuals are expected to be healthy carriers of a CYP4V2 mutation. The estimated genetic prevalence of BCD is about 1:116,000, and we predict that ∼67,000 individuals are affected with BCD worldwide. Translational Relevance: This analysis is likely to have important implications for genetic counseling in each studied population and for developing clinical trials for potential BCD treatments.

A patient advocating for transparent science in rare disease research.

300 million people live with at least one of 6,000 rare diseases worldwide. However, rare disease research is not always reviewed with scrutiny, making it susceptible to what the author refers to as nontransparent science. Nontransparent science can obscure animal model flaws, misguide medicine regulators and drug developers, delay or frustrate orphan drug development, or waste limited resources for rare disease research. Flawed animal models not only lack pharmacologic relevance, but also give rise to issue of clinical translatability. Sadly, these consequences and risks are grossly overlooked. Nontransparency in science can take many forms, such as premature publication of animal models without clinically significant data, not providing corrections when flaws to the model are discovered, lack of warning of critical study limitations, missing critical control data, questionable data quality, surprising results without a sound explanation, failure to rule out potential factors which may affect study conclusions, lack of sufficient detail for others to replicate the study, dubious authorship and study accountability. Science has no boarders, neither does nontransparent science. Nontransparent science can happen irrespective of the researcher's senority, institutional affiliation or country. As a patient-turned researcher suffering from Bietti crystalline dystrophy (BCD), I use BCD as an example to analyze various forms of nontransparent science in rare disease research. This article analyzes three papers published by different research groups on Cyp4v3-/-, high-fat diet (HFD)-Cyp4v3-/-, and Exon1-Cyp4v3-/- mouse models of BCD. As the discussion probes various forms of nontransparent science, the flaws of these knockout mouse models are uncovered. These mouse models do not mimic BCD in humans nor do they address the lack of Cyp4v3 (murine ortholog of human CYP4V2) expression in wild type (WT) mouse retina which is markedly different from CYP4V2 expression in human retina. Further, this article discusses the impact of nontransparent science on drug development which can lead to significant delays ultimately affecting the patients. Lessons from BCD research can be helpful to all those suffering from rare diseases. As a patient, I call for transparent science in rare disease research.