Molecular Genetic Diagnosis with Targeted Next Generation Sequencing in a Cohort of Turkish Osteogenesis Imperfecta Patients and their Genotype-phenotype Correlation
Samim Özen1, Damla Gökşen1, Ferda Evin2, Esra Işık3, Hüseyin Onay4, Bilçağ Akgün4, Aysun Ata1, Tahir Atik3, Füsun Düzcan5, Ferda Özkınay3, Şükran Darcan1, Özgür Çoğulu31Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, İzmir, Turkey2Bakırçay University, Çiğli Training and Research Hospital, Clinic of Pediatric Endocrinology, İzmir, Turkey
3Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Genetics, İzmir, Turkey
4Ege University Faculty of Medicine, Department of Medical Genetics, İzmir, Turkey
5Tınaztepe University Faculty of Medicine, Department of Medical Genetics, İzmir, Turkey
INTRODUCTION: Osteogenesis imperfecta (OI) consists of a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. The aim was to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype in OI patients using targeted next-generation sequencing (NGS).
METHODS: A targeted NGS analysis panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform in patients with a confirmed diagnosis of OI.
RESULTS: Fifty-six patients (female/male: 25/31) from 46 different families were included. Consanguinity was noted in 15 (32.6%) families. Based on Sillence classification 18 (33.1%) were type 1 OI, 1 (1.7%) type 2, 26 (46.4%) type 3 and 11 (19.6%) type 4. Median body weight was -1.1 (-6.8, - 2.5) standard deviation scores (SDS), and height was -2.3 (-7.6, - 1.2) SDS. Bone deformity affected 30 (53.5%), while 31 (55.4%) were evaluated as mobile. Thirty-six (60.7%) had blue sclera, 13 (23.2%) had scoliosis, 12 (21.4%) had dentinogenesis imperfecta (DI), and 2 (3.6%) had hearing loss. Disease-causing variants in COL1A1 and COL1A2 were found in 24 (52.1%) and 6 (13%) families, respectively. In 8 (17.3%) of the remaining 16 (34.7%) families, the NGS panel revealed disease-causing variants in three different genes (FKBP10, SERPINF1, and P3H1). Nine (23.6%) of the variants detected by NGS panel had not previously been reported and were also classified as pathogenic based on American College of Medical Genetics guidelines pathogenity scores. In ten (21.7%) families, a disease-related variant was not found in any of the 13 OI genes on the panel.
DISCUSSION AND CONCLUSION: Genetic etiology was found in 38 (82.6%) of 46 families by targeted NGS analysis. Furthermore, nine new variants were identified in known OI genes which were classified as pathogenic by standard guidelines.
Manuscript Language: English
