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Genotype-phenotype relationship in a large cohort of osteogenesis imperfecta patients with COL1A1 mutations revealed by a new scoring system.
Chin Med J (Engl). 2019 Jan 20; 132(2):145-153.CM

Abstract

BACKGROUND

Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen. This study aimed to investigate the COL1A1 mutation spectrum and quantitatively assess the genotype-phenotype relationship in a large cohort of Chinese patients with OI.

METHODS

A total of 161 patients who were diagnosed as OI in Department of Endocrinology of Peking Union Medical College Hospital from January 2010 to December 2017 were included in the study. The COL1A1 mutation spectrum was identified by next generation sequencing and confirmed by Sanger sequencing. A new clinical scoring system was developed to quantitatively assess the clinical severity of OI and the genotype-phenotype relationship was analyzed. The independent sample t-test, analysis of variance, Mann-Whitney U-test, Chi-squared test, Pearson correlation, and multiple linear regression were applied for statistical analyses.

RESULTS

Among 161 patients with OI, 32.9% missense mutations, 16.8% non-sense mutations, 24.2% splice-site mutations, 24.8% frameshift mutations, and 1.2% whole-gene deletions were identified, of which 38 variations were novel. These mutations led to 53 patients carrying qualitative defects and 67 patients carrying quantitative defects in type I collagen. Compared to patients with quantitative mutations, patients with qualitative mutations had lower alkaline phosphatase level (296 [132, 346] U/L vs. 218 [136, 284] U/L, P = 0.009) and higher clinical score (12.2 ± 5.3 vs. 7.4 ± 2.4, P < 0.001), denoting more severe phenotypes including shorter stature, lower bone mineral density, higher fracture frequency, more bone deformity, vertebral compressive fractures, limited movement, and dentinogenesis imperfecta (DI). Patients would not present with DI if the glycine substitutions happened before the 79th amino acid in triple helix of α1 chains.

CONCLUSIONS

This presented distinctive COL1A1 mutation spectrum in a large cohort of Chinese patients with OI. This new quantitative analysis of genotype-phenotype correlation would be helpful to predict the prognosis of OI and genetic counseling.

Authors+Show Affiliations

Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30614853

Citation

Li, Lu-Jiao, et al. "Genotype-phenotype Relationship in a Large Cohort of Osteogenesis Imperfecta Patients With COL1A1 Mutations Revealed By a New Scoring System." Chinese Medical Journal, vol. 132, no. 2, 2019, pp. 145-153.
Li LJ, Lyu F, Song YW, et al. Genotype-phenotype relationship in a large cohort of osteogenesis imperfecta patients with COL1A1 mutations revealed by a new scoring system. Chin Med J (Engl). 2019;132(2):145-153.
Li, L. J., Lyu, F., Song, Y. W., Wang, O., Jiang, Y., Xia, W. B., Xing, X. P., & Li, M. (2019). Genotype-phenotype relationship in a large cohort of osteogenesis imperfecta patients with COL1A1 mutations revealed by a new scoring system. Chinese Medical Journal, 132(2), 145-153. https://doi.org/10.1097/CM9.0000000000000013
Li LJ, et al. Genotype-phenotype Relationship in a Large Cohort of Osteogenesis Imperfecta Patients With COL1A1 Mutations Revealed By a New Scoring System. Chin Med J (Engl). 2019 Jan 20;132(2):145-153. PubMed PMID: 30614853.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genotype-phenotype relationship in a large cohort of osteogenesis imperfecta patients with COL1A1 mutations revealed by a new scoring system. AU - Li,Lu-Jiao, AU - Lyu,Fang, AU - Song,Yu-Wen, AU - Wang,Ou, AU - Jiang,Yan, AU - Xia,Wei-Bo, AU - Xing,Xiao-Ping, AU - Li,Mei, PY - 2019/1/8/pubmed PY - 2019/4/30/medline PY - 2019/1/8/entrez SP - 145 EP - 153 JF - Chinese medical journal JO - Chin Med J (Engl) VL - 132 IS - 2 N2 - BACKGROUND: Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen. This study aimed to investigate the COL1A1 mutation spectrum and quantitatively assess the genotype-phenotype relationship in a large cohort of Chinese patients with OI. METHODS: A total of 161 patients who were diagnosed as OI in Department of Endocrinology of Peking Union Medical College Hospital from January 2010 to December 2017 were included in the study. The COL1A1 mutation spectrum was identified by next generation sequencing and confirmed by Sanger sequencing. A new clinical scoring system was developed to quantitatively assess the clinical severity of OI and the genotype-phenotype relationship was analyzed. The independent sample t-test, analysis of variance, Mann-Whitney U-test, Chi-squared test, Pearson correlation, and multiple linear regression were applied for statistical analyses. RESULTS: Among 161 patients with OI, 32.9% missense mutations, 16.8% non-sense mutations, 24.2% splice-site mutations, 24.8% frameshift mutations, and 1.2% whole-gene deletions were identified, of which 38 variations were novel. These mutations led to 53 patients carrying qualitative defects and 67 patients carrying quantitative defects in type I collagen. Compared to patients with quantitative mutations, patients with qualitative mutations had lower alkaline phosphatase level (296 [132, 346] U/L vs. 218 [136, 284] U/L, P = 0.009) and higher clinical score (12.2 ± 5.3 vs. 7.4 ± 2.4, P < 0.001), denoting more severe phenotypes including shorter stature, lower bone mineral density, higher fracture frequency, more bone deformity, vertebral compressive fractures, limited movement, and dentinogenesis imperfecta (DI). Patients would not present with DI if the glycine substitutions happened before the 79th amino acid in triple helix of α1 chains. CONCLUSIONS: This presented distinctive COL1A1 mutation spectrum in a large cohort of Chinese patients with OI. This new quantitative analysis of genotype-phenotype correlation would be helpful to predict the prognosis of OI and genetic counseling. SN - 2542-5641 UR - https://www.unboundmedicine.com/medline/citation/30614853/Genotype_phenotype_relationship_in_a_large_cohort_of_osteogenesis_imperfecta_patients_with_COL1A1_mutations_revealed_by_a_new_scoring_system_ L2 - https://doi.org/10.1097/CM9.0000000000000013 DB - PRIME DP - Unbound Medicine ER -