Estimation of PEX1-mediated Zellweger spectrum disorder births and population prevalence by population genetics modeling

Abstract

Purpose: Zellweger Spectrum Disorder (ZSD) is a rare syndromic disorder characterized by impaired peroxisome assembly and function. Many cases are due to pathogenic variants in the PEX1 gene and are inherited in an autosomal recessive manner. As with many rare diseases, understanding the disease burden and scale of unmet need is challenging but required to support diagnosis, disease management, and development of therapies. We present a population-genetics-based model to estimate births and overall disease prevalence for patients in the United States, European countries, and Japan.

Methods: We utilized large-scale genetic diversity data sets to estimate the mutational burden per region and integrated genotype-phenotype relationships with real-world survival data to provide patient number estimates for severe, intermediate, and mild segments per age and country.

Results: We observed regional differences in the variant landscapes expected to contribute to PEX1-mediated ZSD (PEX1-ZSD). Conservative prevalence estimates for the United States, United Kingdom, Germany, France, Italy, Spain, and Japan based solely on known pathogenic variants indicates nearly 500 patients in total. Incorporating predicted pathogenic variants into our model suggests an additional 260 patients with intermediate phenotype and 930 patients with mild phenotype, under the age of 30, across these countries.

Conclusion: Notably, our model indicates that a significant proportion of patients with intermediate/mild phenotype may go unrecognized by current diagnostic practices. This diagnosis independent model of patient number estimates provides additional insights into the broad spectrum of PEX1-ZSD on a more global scale and can be used to inform health care strategies for these patients.

Keywords: Heimler syndrome; PEX1; Peroxisome biogenesis factor 1; Zellweger spectrum disorder.

Graphical abstract

Figure 1

Minor allele frequencies in representative cohorts. A. The minor allele frequencies detected in the representative cohorts for the most pervasive pathogenic variants; JPN_UNI: aggregated data from TogoVAR; gnomad_NFE_S: non-Finnish European, Southern Europe subcohort; gnomad_NFE-NW: non-Finnish European, Northwestern Europe subcohort. Note. Variant p.(Arg633Ter) is also detected in western cohorts at very low frequency but is not readily visualized in this graph. B. Contour map of the variant allele frequencies across Europe for the most pervasive variants.

Figure 2

Summary of the contribution of variants, both known and predicted pathogenic, applied to the population genetics-based models for PEX1-driven ZSD by region. ZSD, Zellweger spectrum disorder.

Figure 3

Expected genotype proportions and phenotypes at birth and ZSDprevalence by age and expected phenotype in the United States. A. Proportions of genotypes expected at birth in the United States and their corresponding expected phenotypes. Missense∗ denotes all other known pathogenic missense variants except G843D. B. Estimated current prevalence of all PEX1-driven ZSD patients in the United States stratified by age and expected phenotype. ZSD, Zellweger spectrum disorder.

Figure 4

Summary of the estimated current total prevalence of all PEX1-ZSD patients in the target countries, stratified by expected phenotype. ZSD, Zellweger spectrum disorder.

Figure 5

Comparison of the core equilibrium model with observed patients from the Natural History Study for the United States subcohort. A. Distribution of 61 patients across the United States currently enrolled in the international, Longitudinal Natural History Study (LNHS) (ClinicalTrials.gov ID: NCT01668186). States in light gray indicate no PEX1 patients enrolled. Select states are labeled for orientation. B. Distribution of Genotypes and Phenotypes observed for the PEX1 US subcohort of the LNHS Study. The leftmost column indicates the proportion of phenotypes as classified by clinical criteria described in Bose et al and flows into the corresponding genotype class. Colors indicate the clinical phenotype, with red being severe, purple representing intermediate disease severity, and teal representing mild disease severity. C. Distribution of genotypes observed in the LNHS PEX1 US subcohort compared with the expected proportion of genotypes predicted by the core equilibrium model for the United States.

Supplemental Figure 1