Rare Causes of Osteogenesis Imperfecta are Common in ...
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58ESPE Poster presented at: Background Osteogenesis imperfecta (OI) : Low bone mass and bone fragility Mainly due to COL1A1/COL1A2 gene defects. >17 genes have been identified in the pathogenesis Aim: Characterize genotypic spectrum of our OI cohort. Methods 47 OI patients (28 males) 38 different families (13 consanguineous/9 multiplex) Screened with the next-generation sequencing (NGS) panel for 15 OI genes Sanger sequencing was used for confirmation and segregation analyses Sillence classification was used to define clinical severity Results COL1A1: 19 patients (15 families): 14 different mutation, 4 novel COL1A2: 3 patients (3 families): 3 different mutations FKBP10: 9 patients (6 families): 4 patients (2 families ) also had Epidermolysis Bullosa Founder mutations: FKBP10 (p.Met107_Leu117del) /KRT14 (p.Tyr204*) 4 patients (4 families ) had 3 novel FKBP10 mutations 2 Siblings (1 OI-III and 1 BS): p.Ser8Glnfs*67 SPARC: 2 patients (1 family): Novel homozygous mutation P3H1: 3 patients (3 families): Novel homozygous mutation Typical features of round face and long fingers. IFITM5: 1 patient; paternally inherited heterozygous WNT1: 1 patient with congenital ptosis CRTAP: 1 patient: Novel homozygous BMP1: 2 patients (1 Family) Rare Causes of Osteogenesis Imperfecta are Common in Consanguineous Pedigrees Sare Betul Kaygusuz 1 , Ahmet Arman 2 , Saygin Abali 3, Pınar Ata 2, Tarık Kırkgoz 1 , Mehmet Eltan 1, Zehra Abali 1, Didem Helvacioglu 1, Busra Tosun 1, Tuba Menevse 1, Tulay Guran 1 , Abdullah Bereket 1, Serap Turan 1 A 1 Marmara University, Department of Pediatrics, Division of Pediatric Endocrinology, Istanbul, Turkey 2 Marmara University, Department of Medical Genetics, Istanbul, Turkey 3 Acibadem University, Department of Pediatrics, Division of Pediatric Sillence Type Gene 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+1G>C 12(6/6) 12 6 COL1A2 p.Gly601Ser, IVS15-2A>G 2 (2/0) 2 2 Unknown 1(1/0) 1 0 OI-II COL1A1 p.Gly704Ser 1(1/0) 1 NE OI-III FKBP10 p.Met107_Leu117del p.Gly300Ter p.Leu105_Arg115del p.Ser8Glnfs*67 8 (5/3) 4 2 COL1A1 p.Gly1076Ser p.Gly413Leufs*122 2 (0/2) 2 NE SPARC p.Glu54Ter 2 (1/1) 2 0 P3H1 p.Met206Ile, c.941-1G>A 2 (1/1) 3 2 COL1A2 p.Gly773Ser 1(1/0) 1 1 WNT1 p.His267Profs*30 1(1/0) 1 1 LRP5 1(1/0) *pseudoglioma 1 SERPINF1 p.Ile301Argfs*21 1(1/0) 0 1 OI-IV COL1A1 p.Gly218Asp, p.Arg598Ter 4 (0/4) 4 3 CRTAP p.Glu179Ter 1(1/0) 1 1 BMP1 p.Arg371His 2(2/0) 0 0 P3H1 p.Leu149Arg 1(0/1) 1 0 Unkonwn 3(3/0) 3 1 OI-V IFITM5 c.-14C > T 1(0/1) 1 1 Bruck Syndrome Type 1 FKBP10 p.Ser8Glnfs*67 1(1/0) 1 1 N individuals 0 5 10 15 20 COL1A1 FKBP10 COL1A2 P3H1 SPARC BMP1 WNT1 LRP5 SERPINF1 CRTAP IFITM5 1 1 1 2 1 4 1 1 1 2 2 1 8 2 1 2 12 Sillence Type 1 Sillence Type 2 Sillence Type 3 Sillence Type 4 Sillence Type 5 Bruck S IFITM5 %2 CRTAP %2 SERPINF1 %2 LRP5 %2 WNT1 %2 BMP1 %5 SPARC %5 P3H1 %7 COL1A2 %7 FKBP10 %21 COL1A1 %44 Figure 1: Mutation analysis of patients Conclusions We were able to identify the molecular etiology in 79% of our OI cohort by NGS panel. We detected 15 novel mutations in 7 different genes. 49% of the defects were in non- COL1A1/COL1A2 genes and 80% of them coming from consanguineous families. Although COL1A1 and COL1A2 gene defects were the most common molecular etiologies,we have identified relatively higher frequencies of rare genetic causes of OI in our cohort. Rare causes of OI should be considered particularly in cases with consanguineous parents and/or with associated abnormalities. A B C D E Figure 3: Phenotypic characteristics of patients: A, B- Patient with LEPRE mutation with round face,short barrel shaped chest, shortening of the long bones. C- Patient with co-segregated FKBP10 and KRT14 with epidermolysis bullosa. D- Forearm radiograph of patient with IFITM5 mutation showing calcification of the interosseous membrane between the radius and ulna (white arrow). E- Patient with congenital bilateral ptosis had WNT1 mutation. Figure 2: Relationship between clinical sillence types and gene mutations Table 1: Mutation analysis and phenotypic characteristics of patients P1-175 P1-175 Sare Betul Kaygusuz DOI: 10.3252/pso.eu.58ESPE.2019 Bone, growth plate and mineral metabolism
Transcript of Rare Causes of Osteogenesis Imperfecta are Common in ...
58ES
PE
Poster presented at:
Background Osteogenesis imperfecta (OI) :
Low bone mass and bone fragility Mainly due to COL1A1/COL1A2 gene defects. >17 genes have been identified in the pathogenesis
Aim: Characterize genotypic spectrum of our OI cohort.
Methods 47 OI patients (28 males) 38 different families (13 consanguineous/9 multiplex) Screened with the next-generation sequencing (NGS) panel for 15 OI genes Sanger sequencing was used for confirmation and segregation analyses Sillence classification was used to define clinical severity
Results COL1A1: 19 patients (15 families): 14 different mutation, 4 novel COL1A2: 3 patients (3 families): 3 different mutations FKBP10: 9 patients (6 families):
4 patients (2 families ) also had Epidermolysis Bullosa Founder mutations: FKBP10 (p.Met107_Leu117del) /KRT14 (p.Tyr204*)
4 patients (4 families ) had 3 novel FKBP10 mutations 2 Siblings (1 OI-III and 1 BS): p.Ser8Glnfs*67
SPARC: 2 patients (1 family): Novel homozygous mutation P3H1: 3 patients (3 families): Novel homozygous mutation
Typical features of round face and long fingers. IFITM5: 1 patient; paternally inherited heterozygous WNT1: 1 patient with congenital ptosis CRTAP: 1 patient: Novel homozygous BMP1: 2 patients (1 Family)
Rare Causes of Osteogenesis Imperfecta are Common in Consanguineous Pedigrees
Sare Betul Kaygusuz1, Ahmet Arman2, Saygin Abali3, Pınar Ata2, Tarık Kırkgoz1, Mehmet Eltan1, Zehra Abali1,
Didem Helvacioglu1, Busra Tosun1, Tuba Menevse1, Tulay Guran1, Abdullah Bereket1, Serap Turan1
A
1Marmara University, Department of Pediatrics, Division of Pediatric Endocrinology, Istanbul, Turkey 2Marmara University, Department of Medical Genetics, Istanbul, Turkey
3Acibadem University, Department of Pediatrics, Division of Pediatric
Sillence Type Gene 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+1G>C
12(6/6) 12 6
COL1A2 p.Gly601Ser, IVS15-2A>G
2 (2/0) 2 2
Unknown 1(1/0) 1 0
OI-IICOL1A1 p.Gly704Ser
1(1/0) 1 NE
OI-III
FKBP10 p.Met107_Leu117del p.Gly300Ter p.Leu105_Arg115del p.Ser8Glnfs*67
8 (5/3) 4 2
COL1A1 p.Gly1076Ser p.Gly413Leufs*122
2 (0/2) 2 NE
SPARC p.Glu54Ter
2 (1/1) 2 0
P3H1 p.Met206Ile, c.941-1G>A
2 (1/1) 3 2
COL1A2 p.Gly773Ser
1(1/0) 1 1
WNT1 p.His267Profs*30
1(1/0) 1 1
LRP5 1(1/0) *pseudoglioma 1SERPINF1 p.Ile301Argfs*21
1(1/0) 0 1
OI-IV
COL1A1 p.Gly218Asp, p.Arg598Ter
4 (0/4) 4 3
CRTAP p.Glu179Ter
1(1/0) 1 1
BMP1 p.Arg371His
2(2/0) 0 0
P3H1 p.Leu149Arg
1(0/1) 1 0
Unkonwn 3(3/0) 3 1
OI-VIFITM5 c.-14C > T
1(0/1) 1 1
Bruck Syndrome Type 1
FKBP10 p.Ser8Glnfs*67
1(1/0) 1 1
N in
divi
dual
s
0
5
10
15
20
COL1A1 FKBP10 COL1A2 P3H1 SPARC BMP1 WNT1 LRP5 SERPINF1 CRTAP IFITM5
1
112
1
4
11122
1
8
2
1
2
12
Sillence Type 1 Sillence Type 2 Sillence Type 3 Sillence Type 4 Sillence Type 5 Bruck S
IFITM5%2
CRTAP%2
SERPINF1%2
LRP5%2
WNT1%2
BMP1%5
SPARC%5
P3H1%7
COL1A2%7
FKBP10%21
COL1A1%44
Figure 1: Mutation analysis of patients
Conclusions
We were able to identify the molecular etiology in 79% of our OI cohort by NGS panel. We detected 15 novel mutations in 7 different genes. 49% of the defects were in non- COL1A1/COL1A2 genes and 80% of them coming from consanguineous families. Although COL1A1 and COL1A2 gene defects were the most common molecular etiologies,we have identified relatively higher frequencies of rare genetic causes of OI in our cohort. Rare causes of OI should be considered particularly in cases with consanguineous parents and/or with associated abnormalities.
A
B
C
D EFigure 3: Phenotypic characteristics of patients: A, B- Patient with LEPRE mutation with round face,short barrel shaped chest, shortening of the long bones. C- Patient with co-segregated FKBP10 and KRT14 with epidermolysis bullosa. D- Forearm radiograph of patient with IFITM5 mutation showing calcification of the interosseous membrane between the radius and ulna (white arrow). E- Patient with congenital bilateral ptosis had WNT1 mutation.
Figure 2: Relationship between clinical sillence types and gene mutationsTable 1: Mutation analysis and phenotypic characteristics of patients
P1-175
P1-175Sare Betul Kaygusuz DOI: 10.3252/pso.eu.58ESPE.2019
Bone, growth plate and mineral metabolism
