Heterogeneity of osteogenesis imperfecta. Biochemical and morphological findings in a case of type III according to Sillence.

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Abstract

[Indexed for MEDLINE] 12. Clin Transl Sci. 2020 Sep;13(5):960-971. doi: 10.1111/cts.12783. Epub 2020 Apr 3. Inter- and Intrafamilial Phenotypic Variability in Individuals with Collagen-Related Osteogenesis Imperfecta. Zhytnik L(1), Maasalu K(1)(2), Reimand T(3)(4)(5), Duy BH(6), Kõks S(7), Märtson A(1)(2). Author information: (1)Department of Traumatology and Orthopedics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia. (2)Clinic of Traumatology and Orthopedics, Tartu University Hospital, Tartu, Estonia. (3)Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia. (4)Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia. (5)Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia. (6)Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam. (7)Perron Institute for Neurological and Translational Science, QEII Medical Centre, Nedlands, Western Australia, Australia. Osteogenesis imperfecta (OI) is a rare genetic disorder also known as a "brittle bone disease." Around 90% of patients with OI harbor loss-of-function or dominant negative pathogenic variants in the COL1A1 and COL1A2 genes, which code for collagen type I α1 and α2 chains. Collagen-related forms of the disorder are classified as Sillence OI types I-IV. OI phenotype expression ranges from mild to lethal. The current study aims to evaluate associations between interfamilial and intrafamilial phenotypic variability and genotype characteristics of patients with collagen-related OI. The study was based on a systematic review of collagen-related OI cases from the University of Tartu OI database (n = 137 individuals from 81 families) and the Dalgleish database (n = 479 individuals). Interfamilial variability analysis has shown that 17.74% of all studied OI-related variants were associated with the same phenotype. The remaining 82.26% of pathogenic variants were associated with variable phenotypes. Additionally, higher interfamilial variability correlated with the COL1A1 gene (P value = 0.001) and dominant-negative variants (P value = 0.0007). Within intrafamilial variability, 32.81% families had increasing or decreasing OI phenotype severity across generations. Higher intrafamilial variability of phenotypes correlated with the collagen I dominant negative variants (P value = 0.0246). The current study shows that, in line with other phenotype modification factors, OI interfamilial and intrafamilial diversity potential is associated with the genotype characteristics of the OI-causing pathogenic variants. The results of the current study may advance knowledge of OI phenotype modification as well as assist family planning and the evaluation of disease progression in subsequent generations. © 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. DOI: 10.1111/cts.12783 PMCID: PMC7485955