Osteogenesis imperfecta in 140 Turkish families:​ molecular spectrum and, comparison of long-term clinical outcome of those with <em>col1a1/a2</em> and biallelic variants

Tüysüz, Beyhan<sup>1</sup>; Elkanova, Leyla<sup>1</sup>; Uludağ Alkaya, Dilek<sup>1</sup>; Güleç, Çağrı<sup>2</sup>; Toksoy, Güven<sup>2</sup>; Güneş, Nilay<sup>1</sup>; Yazan, Hakan<sup>1</sup>; Bayhan, A. Ilhan<sup>3</sup>; Yıldırım, Timur<sup>3</sup>; Yeşil, Gözde<sup>4</sup>; Uyguner, Z. Oya<sup>2</sup>

Affiliations

¹Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey

²Department of Medical Genetics, Istanbul University, Medical Faculty, Istanbul, Turkey

³Department of Orthopedics and Traumatology, University of Health Sciences Turkey, Baltalimani Bone Diseases Training and Research Center, Istanbul, Turkey

⁴Department of Medical Genetics, Bezmialem University, Istanbul, Turkey

Abstract and keywords

Background: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by increased bone fragility and deformities. Although most patients with OI have heterozygous mutations in COL1A1 or COL1A2, 17 genes have been reported to cause OI, most of which are autosomal recessive (AR) inherited, during the last years. The aim of this study is to determine the mutation spectrum in Turkish OI cohort and to investigate the genotype-phenotype correlation.

Methods: 150 patients from 140 Turkish families with OI phenotype were included in this study. Mutations in OI-related genes were identified using targeted gene panel, MLPA analysis for COL1A1 and whole exome sequencing. 113 patients who had OI disease-causing variants were followed for 1–20 years.

Results: OI disease-causing variants were detected in 117 families, of which 62.4% in COL1A1/A2, 35.9% in AR-related genes. A heterozygous variant in IFITM5 and a hemizygous in MBTPS2 were also described, one in each patient. Eighteen biallelic variants (13 novel) were identified in nine genes (FKBP10, P3H1, SERPINF1, TMEM38B, WNT1, BMP1, CRTAP, FAM46A, MESD) among which FKBP10, P3H1 and SERPINF1 were most common. The most severe phenotypes were in patients with FKBP10, SERPINF1, CRTAP, FAM46A and MESD variants. P3H1 patients had moderate, while BMP1 had the mild phenotype. Clinical phenotypes were variable in patients with WNT1 and TMEM38B mutations. We also found mutations in ten ] genes (PLS3, LRP5, ANO5, SLC34A1, EFEMP2, PRDM5, GORAB, OCRL1, TNFRSF11B, DPH1) associated with diseases presenting clinical features which overlap OI, in eleven families.

Conclusion: We identified disease-causing mutations in 83.6% in a large Turkish pediatric OI cohort. 40 novel variants were described. Clinical features and long-term follow-up findings of AR inherited OI types and especially very rare biallelic variants were presented for the first time. Unlike previously reported studies, the mutations that we found in P3H1 were all missense, causing a moderate phenotype.

Keywords: Osteogenesis imperfecta; COL1A1; COL1A2; MLPA; Whole exome sequencing; Autosomal recessive

Links

DOI: 10.1016/j.bone.2021.116293

PubMed: 34902613

WoS: 000773552300015

History

Received: 2021-09-14

Revised: 2021-12-1

Accepted: 2021-12-4

Online: 2021-12-10

Cited Works (5)

Year	Entry
2016	Forlino A, Marini JC. Osteogenesis imperfecta. Lancet. April 16, 2016;387(10028):1657-1671.
2021	Arshad F, Bishop N. Osteogenesis imperfecta in children. Bone. July 2021;148:115914.
2020	Fernandes AM, Rocha-Braz MGM, França MM, Lerario AM, Simões VRF, Zanardo EA, Kulikowski LD, Martin RM, Mendonca BB, Ferraz-de-Souza B. The molecular landscape of osteogenesis imperfecta in a Brazilian tertiary service cohort. Osteoporos Int. July 2020;31(7):1341-1352.
2021	Stürznickel J, Jähn-Rickert K, Zustin J, Hennig F, Delsmann MM, Schoner K, Rehder H, Kreczy A, Schinke T, Amling M, Kornak U, Oheim R. Compound heterozygous frameshift mutations in MESD cause a lethal syndrome suggestive of osteogenesis imperfecta type XX. J Bone Miner Res. June 2021;36(6):1077-1087.
1979	Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;12(2):101-116.

Cited By (1)

Year	Entry
2023	Danyukova T, Alimy A-R, Velho RV, Yorgan TA, Di Lorenzo G, von Kroge S, Tidow H, Wiegert JS, Hermans-Borgmeyer I, Schinke T, Rolvien T, Pohl S. Mice heterozygous for an osteogenesis imperfecta-linked MBTPS2 variant display a compromised subchondral osteocyte lacunocanalicular network associated with abnormal articular cartilage. Bone. December 2023;177:116927.