Background: Osteogenesis imperfecta (OI) is a heterogeneous group of brittle bone disease mostly caused by quantative or qualitative defects in type I collagen. In most populations, more than 90% of the patients with OI have dominant mutations in COL1A1 or COL1A2 genes (AD-OI). Less than 10% of the cases have recessive inheritance (AR-OI). Currently 12 genes have been identified as a cause of AR-OI.
Objective and hypotheses: We assumed higher frequency of AR-OI in our population because of high consanguineous marriages and aimed to detect AR-OI rate and distribution of genetic causes in our cohort.
Method: Eighty-nine patients from 73 families were evaluated for inclusion. The patients having parental OI history (27 families) and/or patients with mutations in COL1A genes (5 families) were excluded because of AD-OI. The patients born to consanguineous parents were included as AR-OI (29 patients/25 families). In AR-OI group, two patients had osteoporosis-pseudoglioma and five patients (four families) had epidermolysis bullosa and found to have founder mutation of p.delGly107_Leu117del in FKBP10 gene. Remaining 19 families were called for genetic analyses. Three patients were died. Whole exome sequencing (WES) was performed to seven index patients.
Results: Novel mutations in LEPRE1, CRTAP and FKBP10 genes were detected in WES We also detected a nonsense mutation in SPARC in two siblings which is a newly described AR-OI gene. Two cousins with severe platyspondily had mutation in BMP1 gene. The other two index cases are still under investigation. Overall, the frequency of recessive OI was 34.2% of the families and 32.6% of the patients.
Conclusion: In our cohort of OI, 1/3 of patients have AR-OI. In 11 families with genetic results, five FKBP10, two LRP5, and one each LEPRE1, CRTAP, BMP1 and SPARC gene mutation have been detected. Distribution of mutations seem to differ from AR-OI cohorts of Spain (n:10) and India (n:7).
10 - 12 Sep 2016
European Society for Paediatric Endocrinology