JCRPE (Dec 2024)

Molecular Genetic Diagnosis with Targeted Next Generation Sequencing in a Cohort of Turkish Osteogenesis Imperfecta Patients and their Genotype-phenotype Correlation

  • Samim Özen,
  • Damla Gökşen,
  • Ferda Evin,
  • Esra Işık,
  • Hüseyin Onay,
  • Bilçağ Akgün,
  • Aysun Ata,
  • Tahir Atik,
  • Füsun Düzcan,
  • Ferda Özkınay,
  • Şükran Darcan,
  • Özgür Çoğulu

DOI
https://doi.org/10.4274/jcrpe.galenos.2024.2022-12-8
Journal volume & issue
Vol. 16, no. 4
pp. 431 – 442

Abstract

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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.

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