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

Tarik Luisman,Shawn Ritchie,Karen E Malone,Tara Smith

doi:10.1186/s13023-021-01889-z

Tarik Luisman, Shawn Ritchie + Show 2 more

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https://doi.org/10.1186/s13023-021-01889-z

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Abstract

BackgroundRhizomelic chondrodysplasia punctata (RCDP) is an inherited ultra-rare disease which results in severely impaired physical and mental development. Mutations in one of five genes involved in plasmalogen biosynthesis have been reported to drive disease pathology. Estimates of disease incidence have been extremely challenging due to the rarity of the disorder, preventing an understanding of the unmet medical need. To address this, we have prepared a disease incidence and prevalence model based on genetic epidemiology approaches to estimate the total number of RCDP patients affected, and their demographic characteristics.ResultsExtraction of allelic frequencies for known and predicted pathogenic variants in PEX7, GNPAT, AGPS, FAR1, PEX5 (limited to the PTS2 domain encoding region) genes, from large-scale human genetic diversity datasets (TopMed and gnomAD) revealed the mutational landscape contributing to the RCDP patient population in the US and Europe. We computed genetic prevalence to derive birth incidence for RCDP and modeled the impact to life expectancy to obtain high confidence estimates of disease prevalence. Our population genetics-based model indicates PEX7 variants are expected to contribute to the majority of RCDP cases in both the US and Europe; closely aligning with clinical reports. Furthermore, this model provides estimates for RCDP subtypes due to mutations in other genes, including exceedingly rare subtypes.ConclusionIn total, the estimated number of RCDP patients in the US and the five largest European countries (UK, Germany, France, Italy and Spain) is between 516 and 847 patients, all under the age of 35 years old. This model provides a quantitative framework for better understanding the unmet medical need in RCDP, to help guide disease awareness and diagnosis efforts for this specific patient group.

Highlights

Rhizomelic chondrodysplasia punctata (RCDP) is an inherited ultra-rare disease which results in severely impaired physical and mental development
The remainder are caused by mutations in one of three genes encoding the peroxisomally active enzymes that perform the initial steps in the plasmalogen biosynthesis pathway: glycerophosphate-O-acyltransferase (GNPAT, RCDP2), alkylglycerone phosphate synthase (AGPS) (RCDP3), and fatty alcohol reductase 1 (FAR1, RCDP4) [8,9,10]
Review of reported variants in genes: PEX7, GNPAT, AGPS, Fatty alcohol reductase 1 (FAR1), and PEX5 in both TopMed and the gnomAD non-Finnish European (NFE) cohort revealed numerous carriers for clinically reported pathogenic variants associated with RCDP

Summary

Introduction

Rhizomelic chondrodysplasia punctata (RCDP) is an inherited ultra-rare disease which results in severely impaired physical and mental development. Mutations in one of five genes involved in plasmalogen biosynthesis have been reported to drive disease pathology. Rhizomelic chondrodysplasia punctata (RCDP) is an ultra-rare inherited disorder caused by an impaired ability to synthesize plasmalogens. RCDP1 is the most common type of RCDP and is caused by mutations in the PEX7 gene, which encodes the PEX7 receptor, responsible for importing alkylglycerone phosphate synthase (AGPS) into the peroxisome [3,4,5,6,7]. A specific mutation in the long isoform of PEX5 was reported in two families and classified as RCDP5 This mutation resulted in impaired binding of PEX5 to the PEX7 receptor, causing problems with peroxisomal targeting [11]. While there is no reported correlation between RCDP type and phenotypic severity, there is a direct correlation between phenotypic severity and residual plasmalogen levels in circulation [2, 6, 12,13,14]

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