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Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants

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Abstract

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 (MED1) are two rare skeletal disorders caused by cartilage oligomeric matrix protein (COMP) variants. This study aims to analyze the genotype and phenotype of patients with COMP variants. Clinical information for 14 probands was collected; DNA was extracted from blood for COMP variant detection. Clinical manifestations and radiology scoring systems were established to evaluate the severity of each patient’s condition. Serum COMP levels in PSACH patients and healthy subjects were measured. Thirty-nine patients were included, along with 12 PSACH probands and two MED1 probands. Disproportionate short stature, waddling gait, early-onset osteoarthritis and skeletal deformities were the most common features. The height Z-score of PSACH patients correlated negatively with age at evaluation (r =  − 0.603, p = 0.01) and the clinical manifestation score (r =  − 0.556, p = 0.039). Over 50% of the PSACH patients were overweight/obese. The median serum COMP level in PSACH patients was 16.75 ng/ml, which was significantly lower than that in healthy controls (98.53 ng/ml; p < 0.001). The condition of MED1 patients was better than that of PSACH patients. Four novel variants of COMP were detected: c.874T>C, c.1123_1134del, c.1531G>A, and c.1576G>T. Height Z-scores and serum COMP levels were significantly lower in patients carrying mutations located in calmodulin-like domains 6, 7, and 8. As the two phenotypes overlap to different degrees, PSACH and MED1 are suggested to combine to produce “spondyloepiphyseal dysplasia, COMP type”. Clinical manifestations and radiology scoring systems, serum COMP levels and genotype are important for evaluating patient condition severity.

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Data Availability

The raw datasets generated and/or analyzed during this study are not publicly available but are available from the corresponding author upon reasonable request.

Change history

  • 04 March 2023

    Missing ESM files has been added in the article.

Abbreviations

PSACH:

Pseudoachondroplasia

MED1:

Multiple epiphyseal dysplasia type 1

COMP:

Cartilage oligomeric matrix protein

NTD:

N-terminal domain

T2:

Epidermal-growth factor-like domains

T3:

Calmodulin-like domains

CTD:

C-terminal domain

BMI:

Body mass index

KDOQI:

Kidney Disease Outcomes Quality Initiative

PCR:

Polymerase chain reaction

M ± SD:

Mean ± standard deviation

IQR:

Interquartile range

y.o.:

Years old

GH:

Growth hormone

IGF-1:

Insulin-like growth factor 1

Ca:

Calcium

P:

Phosphorus

ALP:

Alkaline phosphatase

β-CTX:

C-terminal cross-linking telopeptide of type I collagen

25OHD:

25-Hydroxyvitamin D

rhGH:

Recombinant human growth hormone

ER:

Endoplasmic reticulum

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Acknowledgements

Our deepest thanks to all of the participants in this study and Dr. Yuelun Zhang for whose kind help in statistics. This study was supported by the National Natural Science Foundation of China (Nos. 81900811, 81170805, and 81670714), and the Chinese Academy of Medical Sciences-CAMS Innovation Fund for Medical Sciences (CAMS-2016–12 M-3-003).

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Authors and Affiliations

  1. Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China

    Hanting Liang, Yanfang Hou, Qianqian Pang, Yan Jiang, Ou Wang, Mei Li, Xiaoping Xing, Huijuan Zhu & Weibo Xia

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  1. Hanting Liang
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Contributions

WBX designed the study and revised the manuscript. HTL and YFH analyzed the genetic results. HTL draft the manuscript. QQP sampled the serum. YJ, OW, ML, XPX and HJZ collected the clinical information of the patients. HTL and WBX are responsible for the integrity of the data analysis. All authors read and approved the final manuscript.

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Correspondence to Weibo Xia.

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The study was performed with the approval of the Ethics Committee of Peking Union Medical College Hospital (JS-1689).

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Liang, H., Hou, Y., Pang, Q. et al. Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants. Calcif Tissue Int 110, 313–323 (2022). https://doi.org/10.1007/s00223-021-00920-6

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