The first glycine‐to‐tryptophan substitution in the COL1A1 gene identified in a patient with progressively‐deforming Osteogenesis imperfecta

• Published in: Molecular genetics & genomic medicine 2022-08, Vol.10 (8), p.e1996-n/a
• Main Authors: Sałacińska, Kinga, Michałus, Izabela, Pinkier, Iwona, Rutkowska, Lena, Chlebna‐Sokół, Danuta, Jakubowska‐Pietkiewicz, Elżbieta, Kępczyński, Łukasz, Salachna, Dominik, Gach, Agnieszka
• Format: Article
• Language: English
• Subjects: Amino acids; Biomedical materials; Bones; Clinical Report; Clinical Reports; Collagen; collagen type I; Connective tissue diseases; Connective tissues; Fractures; Genes; Genetic disorders; Genomes; Genotype & phenotype; Genotypes; genotype–phenotype correlation; Glycine; Mutation; Next Generation Sequencing; Osteogenesis; Osteogenesis imperfecta; Pathogenesis; Patients; Phenotypes; Software; Substitutes; Tryptophan
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1996

Background Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue with variable phenotype and heterogeneous genetic background. Majority of reported mutations are glycine substitutions, whose clinical outcome ranges from mild to perinatal lethal. The phenotype appears to be influenced by the properties of amino acid side chain and the degree of structural aberration of collagen molecules. Since the genotype–phenotype correlation remains unclear, the severity of mutation is mostly predicted according to previously‐reported cases. Although the number of OI variants is constantly expanding, no glycine‐to‐tryptophan substitutions have been reported in COL1A1 gene. Methods A sample from a 15‐year‐old girl presenting with progressively‐deforming OI type III was tested using an NGS custom gene panel. Multiple bioinformatic and interpretation tools, including mutation databases and conservation analysis, were used for variant classification. The presence of the mutation was verified by Sanger sequencing. Results A novel heterozygous mutation c.733G>T was identified in the COL1A1 gene (p.Gly245Trp). Conclusions The discovery of this novel glycine‐to‐tryptophan substitution located in the COL1A1 gene broadens the spectrum of mutations underlying this rare disease and provides useful information on the clinical outcome of such substitutions. We have identified the first glycine to tryptophan substitution (p.Gly245Trp) located in the COL1A1 gene in a patient with progressively‐deforming type of Osteogenesis imperfecta. The novel variant broadens spectrum of mutations underlying this rare disease and provides useful information on clinical outcome of tryptophan for glycine substitutions.