Prenatal Diagnosis in a Fetus With X-Linked Recessive Chondrodysplasia Punctata: Identification and Functional Study of a Novel Missense Mutation in ARSE

X-Linked recessive chondrodysplasia punctata (CDPX1) is a rare skeletal dysplasia characterized by stippled epiphyses, brachytelephalangy, and nasomaxillary hypoplasia. CDPX1 is caused by function loss of arylsulfatase E (ARSE, also known as ARSL). Pathogenic mutations in ARSE are responsible for CDPX1 in newborns or adults; however, studies have not fully explored prenatal cases. In the current study, a novel missense mutation (c.265A > G) in ARSE was identified in a fetus with short limbs using whole-exome sequencing (WES). Bioinformatic analysis showed that the variant was pathogenic, and RT-qPCR, Western blot, and enzymatic assays were performed to further explore pathogenicity of the variant. The findings showed that the variant decreased transcription and protein expression levels and led to loss of enzymatic activity of the protein. The novel mutation c.265A > G in ARSE was thus the genetic cause for the phenotype presented by the fetus. The current study presents a prenatal case in Chinese population using functional analysis of ARSE, which helps the family to predict recurrence risks for future pregnancies and provides more information for understanding this rare condition. The findings show that WES is a feasible method for prenatal diagnosis of fetuses with CDPX1.

A rare case of proximal short limb dwarfism-rhizomelic chondrodysplasia punctata type-2

Rhizomelic chondrodysplasia punctata (RCDP) is one of the rare peroxisomal disorder (autosomal recessive inheritance) due to altered phytanic acid alpha oxidation and plasmalogen synthesis. RCDP 1 is the most frequent form of RCDP. It is a peroxisomal biosynthesis disorder. RCDP 2 and RCDP 3 are disorders of individual peroxisome enzyme. Authors described a case of RCDP type 2 in a 13 months old girl with characteristic features of typical chondrodysplastic facies, bilateral cataract, rhizomelic shortening of limbs, growth and global developmental delay; radiological features showed epiphyseal stippling. Genetic analysis showed apparent homozygous deletion of c.1848delC after full sequencing of her GNPAT genes.

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

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.