ESPE Abstracts (2019) 92 P1-175

Rare Causes of Osteogenesis Imperfecta are Common in Consanguineous Pedigrees

Sare Betul Kaygusuz1, Ahmet Arman2, Saygin Abali3, Pinar Ata2, Tarik Kirkgoz1, Mehmet Eltan1, Zehra Yavas Abali1, Didem Helvacioglu1, Busra Gurpinar Tosun1, Tuba Seven Menevse1, Tulay Guran1, Abdullah Bereket1, Serap Turan1


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 TypesGene;MutationN individuals M/FBlue Sclera (+)Dentinogenesis Imperfecta (+)
OI-ICOL1A1;p.Gly260Asp,p.Gly329Val,p.Gly560Ser,p.Gln202Ter,p.Ala714Profs*6,p.Ala1256Profs*75,IVS2+1G>A,IVS5+1G>A,IVS17 +1 G>C6/6126
COL1A2;p.Gly601Ser,IVS15-2A>G2/022
Unknown1/010
OI-IICOL1A1;p.Gly704Ser1/01NE
OI-IIICOL1A1;p.Gly1076Ser,p.Gly413Leufs*1220/22NE
COL1A2;p.Gly773Ser1/011
SPARC;p.Glu54*1/010
P3H1;p.Met206Ile,c.941-1G>A1/132
WNT1;p.His267Profs*301/011
LRP51/0*pseudoglioma1
SERPINF1;p.Ile301Argfs*211/001
FKBP10;p.Met107_Leu117del,p.Gly300Ter,p.Leu105_Arg115del,p.Ser8Glnfs*675/342
OI-IVCOL1A1;p.Gly218Asp,p.Arg598Ter0/443
SPARC;p.Glu54*1/120
CRTAP;p.Glu179Ter1/011
BMP1;p.Arg371His2/000
P3H1;p.Leu149Arg0/110
Unkonwn3/031
OI-VIFITM5;c.-14C > T0/111
BruckSyndrome
Type 1
FKBP10;p.Ser8Glnfs*671/011