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

Abstract

Background 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. 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. Results Extraction 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. Conclusion In 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.

Congenital systemic chondrodysplasia in a white lion (Panthera leo)

“…These findings were also observed in the present case. RCDP is an extremely rare genetic disorder caused by an impaired ability to synthesise plasmalogens 20 . Mutations in five genes associated with plasmalogen biosynthesis have been reported to be the underlining pathology of RCDP.…”

“…Mutations in five genes associated with plasmalogen biosynthesis have been reported to be the underlining pathology of RCDP. RCDP1 is the most common type of RCDP defect and is caused by mutations in the PEX7 gene, which encodes the PEX7 receptor responsible for transporting alkylglycerone phosphate synthase into the peroxisome 20 . It was suspected that the symptoms in this lion were caused by systemic chondrodysplasia; however, causative gene mutations were not investigated.…”

A Pex7 Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity—Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1

“…The overall estimated RCDP prevalence rates are between 0.5 and 0.7 cases per 100,000 births in the US and Europe, respectively ( Luisman et al, 2021 ). RCDP can be caused by defects in 5 peroxisomal genes that result in Pls deficiency.…”

A Case of Rhizomelic Chondrodysplasia Punctata in a Neonate

“…CCP is divided into three primary subtypes: the autosomal dominant Conradi-Hunerman type, the X-linked recessive type, and the autosomal recessive rhizomelic type or RCDP [ 1 ]. In Europe and the United States, the autosomal recessive rhizomelic variant of CCP, RCDP, has an estimated incidence of 0.7 and 0.5 cases per 100,000 births, respectively [ 2 ]. There are five recognized types of RCDP: 1 (OMIM 215100), 2 (OMIM 222765), 3 (OMIM 600121), 4, and 5 (OMIM 616716), with type 1 being the most common accounting for almost 90% of cases.…”

“…In addition, respiratory dysfunction is the most common cause of death [ 8 ]. Although the RCDP population is small, it is growing with unmet medical requirements than are currently recognized, necessitating the need for enhanced diagnostic assistance, increased awareness, and therapeutic development efforts [ 2 ]. We aim to discuss the current knowledge on the etiopathogenesis of RCDP as well as the radiological and clinical symptoms of associated diseases.…”