Genetic basis of osteogenesis imperfecta from a single tertiary centre in South Africa

Abstract

AbstractOsteogenesis imperfecta (OI) is a clinically heterogeneous disorder characterised by skeletal fragility and an increased fracture incidence. It occurs in approximately one in every 15–20,000 births and is known to vary considerably in its severity. This report aimed to use next-generation sequencing (NGS) technology to identify disease genes and causal variants in South African patients with clinical-radiological features of OI. A total of 50 affected individuals were recruited at Tygerberg Hospital’s Medical Genetics clinic. Patients were selected for a gene panel test (n = 39), a single variant test (n = 1) or exome sequencing (ES) (n = 12, 7 singletons, 1 affected duo, and 1 trio), depending on funding eligibility. An in-house genomic bioinformatics pipeline was developed for the ES samples using open-source software and tools. This study’s 100% diagnostic yield was largely attributable to an accurate clinical diagnosis. A causal variant in COL1A1 or COL1A2 was identified in 94% of this patient cohort, which is in line with previous studies. Interestingly, this study was the first to identify the common South African pathogenic FKBP10 variant in a patient of mixed ancestry, adding to what was previously known about this variant in our population. Additionally, a recurrent variant in COL1A2: c.1892G>T was discovered in 27 individuals (25 from three large unrelated families and two further individuals), facilitating the establishment of local testing for this variant in South African patients.