From Genetics to Clinical Implications: A Study of 675 Dutch Osteogenesis Imperfecta Patients

Abstract

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that causes bone fragility due to pathogenic variants in genes responsible for the synthesis of type I collagen. Efforts to classify the high clinical variability in OI led to the Sillence classification. However, this classification only partially takes into account extraskeletal manifestations and the high genetic variability. Little is known about the relation between genetic variants and phenotype as of yet. The aim of the study was to create a clinically relevant genetic stratification of a cohort of 675 Dutch OI patients based on their pathogenic variant types and to provide an overview of their respective medical care demands. The clinical records of 675 OI patients were extracted from the Amsterdam UMC Genome Database and matched with the records from Statistics Netherlands (CBS). The patients were categorized based on their harbored pathogenic variant. The information on hospital admissions, outpatient clinic visits, medication, and diagnosis-treatment combinations (DTCs) was compared between the variant groups. OI patients in the Netherlands appear to have a higher number of DTCs, outpatient clinic visits, and hospital admissions when compared to the general Dutch population. Furthermore, medication usage seems higher in the OI cohort in comparison to the general population. The patients with a COL1A1 or COL1A2 dominant negative missense non-glycine substitution appear to have a lower health care need compared to the other groups, and even lower than patients with COL1A1 or COL1A2 haploinsufficiency. It would be useful to include the variant type in addition to the Sillence classification when categorizing a patient’s phenotype.

The IMPACT survey: a mixed methods study to understand the experience of children, adolescents and adults with osteogenesis imperfecta and their caregivers

“…This finding mirrors previous research and suggests that “severity” is a holistic, patient-centric view of individuals’ health, that is not entirely captured by the clinical OI type which is determined based on clinical and molecular patient characteristics [ 20 , 21 ]. Additionally, while general predictions about the clinical OI type can be made based on the causative gene, mutation type and location, genetic variation alone does not account for all phenotypic variation [ 22 – 24 ].…”

Medical Care Use Among Patients with Monogenic Osteoporosis Due to Rare Variants in LRP5, PLS3, or WNT1

“…As biallelic pathogenic variants in WNT1 are known to cause a severe form of OI, individuals with these variants were excluded. The Dutch OI population, which has been previously described and also comes from the Amsterdam UMC genome database, was used to compare individuals with LRP5 , PLS3 , or WNT1 mutations to OI patients [ 22 , 25 ].…”

“…The CBS website provides free public access to information on the number of hospital admissions and DTCs in the Dutch population each year [ 29 , 30 ]. In addition, the number of hospital admissions was compared to the number of admissions in the Dutch OI population [ 25 ]. The numerator of the IRRs was the mean number of admissions or DTCs per year in the LRP5 , PLS3 , and WNT1 cohort, while the denominator was the mean found in the total population or the OI population.…”

Discrepancies in the Phenotypical Classification of Osteogenesis Imperfecta in a Patient with COL1A2 Mutation: A Case Report

“…Osteogenesis imperfecta (OI) is a rare connective tissue genetic disorder caused by inherited and sporadic mutations in type I collagen or proteins that interact with it [ 1 ]. Type I collagen is a molecule composed of two α1(I) chains and one α2(I) chain.…”

“…It is hypothesized that in COL1A2 mutations in which glycine is substituted by another amino acid such as alanine, valine, or serine, there is a disruption of the alpha-helix structure, leading to defective binding of interacting proteins resulting in aberrant function [ 2 ]. The clinical picture of OI includes bone fragility, decreased bone density, short stature, early loss of hearing, and, in some cases, dentinogenesis imperfecta (DI), a dentin defect [ 1 , 3 ]. The incidence of this disease is estimated to be approximately 1 in 15 000 to 20 000 births [ 4 ].…”