Inter‐ and Intrafamilial Phenotypic Variability in Individuals with Collagen‐Related Osteogenesis Imperfecta

Abstract

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 OIrelated 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. Osteogenesis imperfecta (OI) is a heterogenous spectrum of rare, congenital bone fragility disorders. 1 The general prevalence of OI is 1/10-20,000. 2,3 A majority of patients with OI (90%) harbor autosomal dominant pathogenic variants in the COL1A1 and COL1A2 genes, which encode α1 and α2 chains of type I collagen. 4 The loss-of-function (LOF) pathogenic variants in type I collagen genes lead to reduced production of collagen, but the structure of the molecules is not altered. Missense pathogenic variants lead to a dominant-negative (DN) effect and abnormal structure of collagen type I. 5 OI is characterized by frequent fractures, skeletal deformities, blue sclera, and hearing loss. In addition, patients

Phenotypic Spectrum and Molecular Basis in a Chinese Cohort of Osteogenesis Imperfecta With Mutations in Type I Collagen

“…Interestingly, remarkable phenotypic variability ranging from moderate to severe was observed among individuals bearing this variant (Supplementary Figure S4). It was recently suggested that haploinsufficiency in familial cases may cause similar features, whereas structural abnormality results in higher phenotypic variability (Zhytnik et al, 2020).…”

Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive P3H1 Pathogenic Variant

“…It remains to be seen if the discovery of more missense pathogenic variants will further uncover more about the milder end of the P3H1 clinical spectrum. Additionally, the severity of P3H1 -related OI might also be influenced by modifying factors and epigenetics, as it is in the case of other OI forms [ 4 , 31 , 32 , 33 , 34 ].…”

Collagen transport and related pathways in Osteogenesis Imperfecta

“…This review recapitulates our understanding of collagen trafficking, highlighting the significance of anterograde and retrograde transport. Based on the current state of knowledge in this review of the literature (Table 1 ), limited conclusions can be drawn on genotype–phenotype correlations which points to the fact that we still need to understand critical factors in the regulating mechanism as well as intrafamilial and interfamilial OI variation (Forlino and Marini 2016 ; Zhytnik et al 2020 ). This variation is also reflected in the international Osteogenesis Imperfecta Variant Database where individual mutations can lead to different clinical OI types ( https://oi.gene.le.ac.uk ).…”