Abstract
Osteogenesis imperfecta (OI) is a syndromic disorder of bone fragility with high variation in its clinical presentation. Equally variable is molecular aetiology; recessive forms are caused by approximately 20 different genes, many of which are directly implicated in collagen type I biosynthesis. Biallelic variants in prolyl 3-hydroxylase 1 (P3H1) are known to cause severe OI by affecting the competence of the prolyl 3-hydroxylation—cartilage associated protein—peptidyl-prolyl cis-trans isomerase B (P3H1-CRTAP-CyPB) complex, which acts on the Pro986 residue of collagen type I α 1 (COL1A1) and Pro707 collagen type I α 2 (COL1A2) chains. The investigation of an OI cohort of 146 patients in Vietnam identified 14 families with P3H1 variants. The c.1170+5G>C variant was found to be very prevalent (12/14) and accounted for 10.3% of the Vietnamese OI cohort. New P3H1 variants were also identified in this population. Interestingly, the c.1170+5G>C variants were found in families with the severe clinical Sillence types 2 and 3 but also the milder types 1 and 4. This is the first time that OI type 1 is reported in patients with P3H1 variants expanding the clinical spectrum. Patients with a homozygous c.1170+5G>C variant shared severe progressively deforming OI type 3: bowed long bones, deformities of ribcage, long phalanges and hands, bluish sclera, brachycephaly, and early intrauterine fractures. Although it remains unclear if the c.1170+5G>C variant constitutes a founder mutation in the Vietnamese population, its prevalence makes it valuable for the molecular diagnosis of OI in patients of the Kinh ethnicity. Our study provides insight into the clinical and genetic variation of P3H1-related OI in the Vietnamese population.
Highlights
Osteogenesis imperfecta (OI) is a connective tissue disorder with bone fragility as the predominant feature
Genomic DNA extraction from EDTA-preserved blood and further Sanger sequencing and mutational analysis of the COL1A1, COL1A2, and interferon induced transmembrane ing the interviews with the medical and research team of the University of Tartu in Vietnam, clinical examination and phenotype descriptions were performed, and patients were classified in concordance with the updated clinical Sillence classification
In order to explore the genetic variation in the prolyl 3-hydroxylase 1 (P3H1) gene and possible common haplotype between carriers of the same c.1170+5G>C variant, we examined the presence of the c.465+489delG and c.465+499delG single nucleotide polymorphisms (SNPs) in the 14 index patients
Summary
Osteogenesis imperfecta (OI) is a connective tissue disorder with bone fragility as the predominant feature. The disease shows a continuum of clinical severity, the heterogeneity of which is reflected by the five clinical Sillence classification types [1,2]. Type 1 (OMIM#: 166200) is the mild end of the spectrum and includes patients who can experience a variable number of bone fractures with very minimal skeletal dysplasia [3]. Is the most severe form of OI, with patients succumbing to perinatal death due to severe skeletal dysplasia [3]. Type 3 (OMIM#: 259420) is the most severe form of adult OI with bone fragility accompanied by progressive skeletal malformations.
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