REVIEW article
Front. Endocrinol.
Sec. Bone Research
Genotype-phenotype correlations in PSACH/EDM1 patients with COMP gene variants: a comprehensive review of 830 cases
Provisionally accepted
- 1Beijing Children's Hospital Capital Medical University, Beijing, China
- 2Peking Union Medical College Hospital (CAMS), Beijing, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Background: Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia-1 (EDM1) are two rare skeletal diseases that represent distinct endpoints of a continuous phenotypic spectrum with substantial clinical overlap, caused by variants in the gene coding cartilage oligomeric matrix protein (COMP). Objectives: To summarize the clinical characteristics of PSACH/EDM1 and variants of COMP gene, as well as to explore the correlations between them. Methods: PubMed, China National Knowledge Infrastructure, and Wanfang were searched for case reports and case series of patients with genetic diagnosis of PSACH/EDM1 from the inception to 24 March 2025. The clinical characteristics and gene variants of enrolled patients were analyzed and compared to explore genotype-phenotype correlation. Results: A total of 830 PSACH/EDM1 patients (471probands) harboring 224 different variants of COMP gene were enrolled from 106 articles, with missense variants accounting for the majority (80.8%). Exon 13 (183 probands, 38.9%) and type III (T3) repeat domain (413 probands, 87.7%) were the most commonly affected regions, with c.1417_1419del (p.Asp473del) being the most common hotspot variant. Compared with EDM1, PSACH manifested earlier age of onset (p < 0.001), shorter stature (p < 0.001), higher rates of lower limb deformity (p < 0.001), joint laxity (p = 0.041), anterior beaking of the vertebra and irregular/flared metaphysis (p < 0.001), while lower rate of joint pain/osteoarthritis (p < 0.001) and abnormal femoral head (p = 0.008). Missense variants in T3-4 and T3-5 were more likely to cause EDM1 (all p < 0.001), while those in T3-1 and T3-6 to T3-8 were associated with a greater frequency of PSACH (p = 0.002 to 0.023). Majority of in-frame variants were found in PSACH, as c.1417_1419del (p.Asp473del) being PSACH specific. Conclusions: PSACH exhibits more severe phenotypes than EDM1, even with phenotypic overlap. In-frame variants are more strongly associated with PSACH, as the hotspot variant p.Asp473del exclusively identified in PSACH. In contrast, missense variants in T3-4 and T3-5 show a stronger association with EDM1.
Keywords: COMP gene, genotype-phenotype correlations, multiple epiphyseal dysplasia-1, Pseudoachondroplasia, variant
Received: 06 Nov 2025; Accepted: 02 Feb 2026.
Copyright: © 2026 Ni, Wei, Xia and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Weibo Xia
Di Wu
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.