Leiden Analytics, Leiden, The Netherlands.
Med-Life Discoveries, Saskatoon, SK, Canada.
Orphanet J Rare Dis. 2021 Jul 6;16(1):300. doi: 10.1186/s13023-021-01889-z.
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.
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.
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.
Rhizomelic 软骨发育不良点状（RCDP）是一种遗传性罕见疾病，导致严重的身体和智力发育受损。据报道，参与磷脂原生物合成的五个基因中的一个基因突变会导致疾病发生。由于该疾病极为罕见，发病估计极具挑战性，这阻碍了对未满足的医疗需求的理解。为了解决这个问题，我们根据遗传流行病学方法，准备了一种疾病发病和流行模型，以估计受影响的 RCDP 患者总数及其人口统计学特征。
从大规模人类遗传多样性数据集（TopMed 和 gnomAD）中提取 PEX7、GNPAT、AGPS、FAR1 和 PEX5（仅限于 PTS2 结构域编码区）基因中已知和预测致病性变异的等位基因频率，揭示了导致美国和欧洲 RCDP 患者人群发生突变的突变景观。我们计算了遗传流行率，以推导出 RCDP 的出生发病率，并对预期寿命进行建模，以获得对疾病流行率的高度置信估计。我们基于群体遗传学的模型表明，PEX7 变异预计将导致美国和欧洲的大多数 RCDP 病例；这与临床报告密切一致。此外，该模型还提供了由于其他基因突变引起的 RCDP 亚型的估计，包括极为罕见的亚型。
总的来说，美国和五个最大的欧洲国家（英国、德国、法国、意大利和西班牙）的 RCDP 患者估计人数在 516 到 847 人之间，所有患者年龄都在 35 岁以下。该模型为更好地理解 RCDP 中的未满足医疗需求提供了一个定量框架，有助于指导针对这一特定患者群体的疾病意识和诊断工作。
