ESPE2019 Poster Category 1 Bone, Growth Plate and Mineral Metabolism (1) (10 abstracts)
Rare Causes of Osteogenesis Imperfecta are Common in Consanguineous Pedigrees
Sare Betul Kaygusuz 1 , Ahmet Arman 2 , Saygin Abali 3 , Pinar Ata 2 , Tarik Kirkgoz 1 , Mehmet Eltan 1 , Zehra Yavas Abali 1 , Didem Helvacioglu 1 , Busra Gurpinar Tosun 1 , Tuba Seven Menevse 1 , Tulay Guran 1 , Abdullah Bereket 1 & Serap Turan 1
1Marmara University Faculty of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey. 2Marmara University Faculty of Medicine, Department of Medical Genetics, Istanbul, Turkey. 3Acibadem University Faculty of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey
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 |
| COL1A2;p.Gly601Ser,IVS15-2A>G | 2/0 | 2 | 2 | |
| Unknown | 1/0 | 1 | 0 | |
| OI-II | COL1A1;p.Gly704Ser | 1/0 | 1 | NE |
| OI-III | COL1A1;p.Gly1076Ser,p.Gly413Leufs*122 | 0/2 | 2 | NE |
| COL1A2;p.Gly773Ser | 1/0 | 1 | 1 | |
| SPARC;p.Glu54* | 1/0 | 1 | 0 | |
| P3H1;p.Met206Ile,c.941-1G>A | 1/1 | 3 | 2 | |
| WNT1;p.His267Profs*30 | 1/0 | 1 | 1 | |
| LRP5 | 1/0 | *pseudoglioma | 1 | |
| SERPINF1;p.Ile301Argfs*21 | 1/0 | 0 | 1 | |
| FKBP10;p.Met107_Leu117del,p.Gly300Ter,p.Leu105_Arg115del,p.Ser8Glnfs*67 | 5/3 | 4 | 2 | |
| OI-IV | COL1A1;p.Gly218Asp,p.Arg598Ter | 0/4 | 4 | 3 |
| SPARC;p.Glu54* | 1/1 | 2 | 0 | |
| CRTAP;p.Glu179Ter | 1/0 | 1 | 1 | |
| BMP1;p.Arg371His | 2/0 | 0 | 0 | |
| P3H1;p.Leu149Arg | 0/1 | 1 | 0 | |
| Unkonwn | 3/0 | 3 | 1 | |
| OI-V | IFITM5;c.-14C > T | 0/1 | 1 | 1 |
| BruckSyndrome Type 1 | FKBP10;p.Ser8Glnfs*67 | 1/0 | 1 | 1 |
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