Molecular Genetic Etiology in Osteogenesis Imperfecta by Whole Exome Sequence Analysis
Project no. 22611 · Status: Kapanmış · 2021
Summary
<p><strong>Introduction:</strong> Osteogenesis imperfecta (OI) is a phenotypically and molecularly heterogeneous group of inherited connective tissue disorders that share similar skeletal abnormalities causing bone fragility and deformity. To date, about 17 genes responsible for OI have been identified. Osteogenesis imperfecta was divided into 4 types clinically, the number of subtypes has increased to 19 in parallel with the genes defined over the years. Variants in the <em>COL1A1 </em>and <em>COL1A2</em> genes encoding type I collagen are responsible for approximately 70-80% of the etiology. Apart from these genes, genes involved in posttranslational modification and intracellular transport of type I collagen were also responsible for the disease. The aim of this study was to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype with targeted whole exome sequence analysis for cases with the OI phenotype.</p><p><strong>Method: </strong>Patients with a diagnosis of OI who had no molecular genetic cause were included in the study. Clinical typing of all patients was performed. Demographic and clinical characteristics were recorded. In the first step, before exome sequencing, MLPA analysis was performed in each case primarily to detect possible large intragenic deletions/duplications in the COL1A1 and COL1A2 genes responsible for most of the disease. Whole exome sequencing was performed in cases in which MLPA was performed and no deletion/duplication was detected. Pathogenicity of determined variants was determined according to ACMG/AMP criteria.</p><p><strong>Results: </strong>Of the 8 patients included in the study, 87.5% had a consanguineous marriage between their parents, and 37.5% had a family history of affected individuals. When the cases were grouped according to clinical types; 3 patients (37.5%) were evaluated as type 1, 4 (50%) as type 3, and 1 (12.5%) as type 4.</p><p>Two different variants were found in the P3H1 gene in one (12.5%) of the cases, in the FKBP10 gene in one (12.5%), and in the WNT1 gene in two (25%) cases. Two (40%) of the variants detected in all investigated genes were novel variant as disease-causing, and clinically unknown variants according to in-silico analysis programs. In four (50%) cases, no pathogenic variant was detected in the analyzed genes. Genetic reanalyzes are ongoing in cases where no variant is detected in any gene.</p>