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Severe cases of osteogenesis imperfecta type VIII due to a homozygous mutation in P3H1 (LEPRE1) and review of the literature
Copyright policy )Severe cases of osteogenesis imperfecta type VIII due to a homozygous mutation in P3H1 (LEPRE1) and review of the literature
BACKGROUND Osteogenesis imperfecta (OI) is a genetic disorder that causes skeletal fragility, multiple fractures and several extraskeletal disorders. Most cases of OI are caused by mutations in COL1A1/A2. Osteogenesis imperfecta type VIII typically causes a severe and fatal phenotype that presents at birth with severe osteopenia, congenital fractures and other clinical manifestations. OBJECTIVES We describe the cases of an 11-year-old female and a 9-year-old male with homozygous truncating mutations in P3H1. Both cases were born with intrauterine fractures and suffered multiple fractures shortly after birth, requiring multiple operations to correct both fractures and severe scoliosis. The patients have been treated with pamidronate since the age of 2. MATERIAL AND METHODS Whole exome sequencing (WES) was performed by Gene by Gene using Twist Bioscience technology. Initially, ~36.5 Mb of consensus coding sequences (targeting >98% of RefSeq and Gencode v. 28 regions obtained from the human genome) was replicated from fragmented genomic DNA using the Twist Human Core Exome Plus kit. The subsequent library was sequenced on the Illumina Novaseq Next Generation Sequencing platform to achieve at least ×20 reading depth for >98% of the targeted bases. Variant annotations and filtering was performed using Ingenuity Variant Analysis software. RESULTS We identified a homozygous mutation in the 3rd exon of P3H1 (c.628C>T/p.Arg210 Ter). Our cases broaden the phenotypic spectrum of OI type VIII as, to the best of our knowledge, these are the first postnatal cases with P3H1 (c.628C>T/p.Arg210 Ter) mutations published in the literature. CONCLUSIONS We present the first recorded postnatal cases from unrelated families of OI type VIII, broadening our understanding of the severe, but nonfatal spectrum of clinical phenotype of this recessive form of OI.
Microsoft Academic Graph classification: Pediatrics medicine.medical_specialty medicine.disease_cause Exon medicine Gene Exome Exome sequencing Mutation business.industry Genetic disorder medicine.disease Osteogenesis imperfecta Human genome business
Male, Medicine (miscellaneous), Prolyl Hydroxylases, General Biochemistry, Genetics and Molecular Biology, Internal Medicine, Humans, Genetics(clinical), Pharmacology (medical), Child, Genetics (clinical), Membrane Glycoproteins, Osteogenesis Imperfecta, Reviews and References, Medical, Mutation, Reviews and References (medical), Female, Proteoglycans
Male, Medicine (miscellaneous), Prolyl Hydroxylases, General Biochemistry, Genetics and Molecular Biology, Internal Medicine, Humans, Genetics(clinical), Pharmacology (medical), Child, Genetics (clinical), Membrane Glycoproteins, Osteogenesis Imperfecta, Reviews and References, Medical, Mutation, Reviews and References (medical), Female, Proteoglycans
Microsoft Academic Graph classification: Pediatrics medicine.medical_specialty medicine.disease_cause Exon medicine Gene Exome Exome sequencing Mutation business.industry Genetic disorder medicine.disease Osteogenesis imperfecta Human genome business
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).2 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Average citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).2 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Average
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BACKGROUND Osteogenesis imperfecta (OI) is a genetic disorder that causes skeletal fragility, multiple fractures and several extraskeletal disorders. Most cases of OI are caused by mutations in COL1A1/A2. Osteogenesis imperfecta type VIII typically causes a severe and fatal phenotype that presents at birth with severe osteopenia, congenital fractures and other clinical manifestations. OBJECTIVES We describe the cases of an 11-year-old female and a 9-year-old male with homozygous truncating mutations in P3H1. Both cases were born with intrauterine fractures and suffered multiple fractures shortly after birth, requiring multiple operations to correct both fractures and severe scoliosis. The patients have been treated with pamidronate since the age of 2. MATERIAL AND METHODS Whole exome sequencing (WES) was performed by Gene by Gene using Twist Bioscience technology. Initially, ~36.5 Mb of consensus coding sequences (targeting >98% of RefSeq and Gencode v. 28 regions obtained from the human genome) was replicated from fragmented genomic DNA using the Twist Human Core Exome Plus kit. The subsequent library was sequenced on the Illumina Novaseq Next Generation Sequencing platform to achieve at least ×20 reading depth for >98% of the targeted bases. Variant annotations and filtering was performed using Ingenuity Variant Analysis software. RESULTS We identified a homozygous mutation in the 3rd exon of P3H1 (c.628C>T/p.Arg210 Ter). Our cases broaden the phenotypic spectrum of OI type VIII as, to the best of our knowledge, these are the first postnatal cases with P3H1 (c.628C>T/p.Arg210 Ter) mutations published in the literature. CONCLUSIONS We present the first recorded postnatal cases from unrelated families of OI type VIII, broadening our understanding of the severe, but nonfatal spectrum of clinical phenotype of this recessive form of OI.