Background: Osteogenesis imperfecta (OI) is characterized by low bone mass and bone fragility mainly due to COL1A1/COL1A2 gene defects. However, >17 genes have been identified in the pathogenesis of OI. Here, we aim to characterize genotypic spectrum of our OI cohort.
Methods: Forty-nine OI patients (28 males) from 38 different families (13 consanguineous/9 multiplex) were screened with the next-generation sequencing (NGS) panel for 15 OI genes and, Sanger sequencing was used for confirmation and segregation analyses. Sillence classification was used to define clinical severity.
Results: We have identified COL1A1 (n:14, 5 novel) and COL1A2 mutations (n:3) in 22 patients from 18 unrelated families. FKBP10 mutations had been detected in 9 patients from 6 families. Four patients from 2 families also had Epidermolysis Bullosa. They had co-segregated founder mutations in FKBP10 (p.Met107_Leu117del) and KRT14 (p.Tyr204*) genes which were reported previously in patients from the same geographical region as our patients. Additional four patients from 4 families had 3 novel FKBP10 mutations, interestingly, one OI-3 patient had a brother with Bruck syndrome who were carrying same mutation.
Three novel homozygous P3H1 mutations had been identified in three patients who had typical features of round face and long fingers. A novel homozygous SPARC mutation was identified in two siblings. We have also identified a paternally inherited heterozygous IFITM5 mutation in one patient. Additionally, a homozygous WNT1 mutation in one patient with congenital ptosis, a novel homozygous mutation in CRTAP in one patient, BMP1 in two patients from one family and SERPINF1 in one patient had been detected (Table).
Conclusions: We were able to identify the molecular etiology in 79% of our OI cohort by NGS panel and detected 15 novel mutations in 7 different genes. And, 35% of the defects were in non-COL1A1/COL1A2genes and 80% of them coming from consanguineous families.
|Sillence Types||Gene;Mutation||N individuals M/F||Blue Sclera (+)||Dentinogenesis Imperfecta (+)|
|OI-I||COL1A1;p.Gly260Asp,p.Gly329Val,p.Gly560Ser,p.Gln202Ter,p.Ala714Profs*6,p.Ala1256Profs*75,IVS2+1G>A,IVS5+1G>A,IVS17 +1 G>C||6/6||12||6|
|OI-V||IFITM5;c.-14C > T||0/1||1||1|
19 - 21 Sep 2019
European Society for Paediatric Endocrinology