From Genetics to Clinical Implications: A Study of 675 Dutch Osteogenesis Imperfecta Patients (original) (raw)
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Background Osteogenesis imperfecta (OI) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations in COL1A1 or COL1A2 and show autosomal dominant inheritance, during the last years there has been an explosion in the number of genes responsible for both recessive and dominant forms of this condition. Herein, we have analyzed a cohort of patients with OI, all offspring of unaffected parents, to determine the spectrum of variants accounting for these cases. Twenty patients had nonrelated parents and were sporadic, and 21 were born to consanguineous relationships. Methods Mutation analysis was performed using a next-generation sequencing gene panel, homozygosity mapping, and whole exome sequencing (WES). Results Patients offspring of nonconsanguineous parents were mostly identified with COL1A1 or COL1A2 heterozygous changes, although there were also a few cases with IFITM5 and WNT1 heterozygous mutations. Only one sporadic patient was a compound heterozygote for two recessive mutations. Patients offspring of consanguineous parents showed homozygous changes in a variety of genes including CRTAP, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, TMEM38B, and WNT1. In addition, two patients born to consanguineous parents were found to have de novo COL1A1 heterozygous mutations demonstrating that causative variants in the collagen I structural genes cannot be overlooked in affected children from consanguineous couples. Further to this, WES analysis in probands 28
2009
Osteogenesis imperfecta (OI), also known as brittle bone disease, is a clinically and genetically heterogeneous disorder primarily characterized by susceptibility to fracture. Although OI generally results from mutations in the type I collagen genes, COL1A1 and COL1A2, the relationship between genotype and phenotype is not yet well understood. To provide additional data for genotype-phenotype analyses and to determine the proportion of mutations in the type I collagen genes among subjects with lethal forms of OI, we sequenced the coding and exon-flanking regions of COL1A1 and COL1A2 in a cohort of 63 subjects with OI type II, the perinatal lethal form of the disease. We identified 61 distinct heterozygous mutations in type I collagen, including five non-synonymous rare variants of unknown significance, of which 43 had not been seen previously. In addition, we found 60 SNPs in COL1A1, of which 17 were not reported previously, and 82 in COL1A2, of which 18 are novel. In three samples without collagen mutations, we found inactivating mutations in CRTAP and LEPRE1, suggesting a frequency of these recessive mutations of 5% in OI type II. A computational model that predicts the outcome of substitutions for glycine within the triple helical domain of collagen a1(I) chains predicted lethality with 90% accuracy. The results contribute to the understanding of the etiology of OI by providing data to evaluate and refine current models relating genotype to phenotype and by providing an unbiased indication of the relative frequency of mutations in OI-associated genes.
Molecular genetics & genomic medicine, 2018
Osteogenesis imperfecta (OI) is a heterogeneous hereditary connective tissue disorder clinically hallmarked by increased susceptibility to bone fractures. We analyzed a cohort of 77 diagnosed OI patients from 49 unrelated Palestinian families. Next-generation sequencing technology was used to screen a panel of known OI genes. In 41 probands, we identified 28 different disease-causing variants of 9 different known OI genes. Eleven of the variants are novel. Ten of the 28 variants are located in COL1A1, five in COL1A2, three in BMP1, three in FKBP10, two in TMEM38B, two in P3H1, and one each in CRTAP, SERPINF1, and SERPINH1. The absence of disease-causing variants in the remaining eight probands suggests further genetic heterogeneity in OI. In general, most OI patients (90%) harbor mainly variants in type I collagen resulting in an autosomal dominant inheritance pattern. However, in our cohort almost 61% (25/41) were affected with autosomal recessive OI. Moreover, we document a 21-kb ...
Genotype–phenotype correlation study in 364 osteogenesis imperfecta Italian patients
European Journal of Human Genetics
Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue and 90% of cases are due to dominant mutations in COL1A1 and COL1A2 genes. To increase OI disease knowledge and contribute to patient follow-up management, a homogeneous Italian cohort of 364 subjects affected by OI types I-IV was evaluated. The study population was composed of 262 OI type I, 24 type II, 39 type III, and 39 type IV patients. Three hundred and nine subjects had a type I collagen affecting function mutations (230 in α1(I) and 79 in α2(I)); no disease-causing changes were noticed in 55 patients. Compared with previous genotype-phenotype OI correlation studies, additional observations arose: a new effect for α1and α2-serine substitutions has been pointed out and heart defects, never considered before, resulted associated to quantitative mutations (P = 0.043). Moreover, some different findings emerged if compared with previous literature; especially, focusing the attention on the lethal form, no association with specific collagen regions was found and most of variants localized in the previously reported "lethal clusters" were causative of OI types I-IV. Some discrepancies have been highlighted also considering the "50-55 nucleotides rule," as well as the relationship between specific collagen I mutated region and the presence of dentinogenesis imperfecta and/or blue sclera. Despite difficulties still present in defining clear rules to predict the clinical outcome in OI patients, this study provides new pieces for completing the puzzle, also thanks to the inclusion of clinical signs never considered before and to the large number of OI Italian patients.
Genotype and phenotype analysis of Taiwanese patients with osteogenesis imperfecta
Orphanet journal of rare diseases, 2015
Osteogenesis imperfecta (OI) is a congenital disorder characterized by increased bone fragility and low bone mass. The presence of COL1A1 or COL1A2 mutation was investigated by direct sequencing in 72 patients with OI type I, III, or IV (27 males and 45 females; age range 0.2-62 years) from 37 unrelated families. The clinical features of these patients were also recorded. Thirty-seven COL1A1 and COL1A2 mutations were identified, including 28 COL1A1 mutations and 9 COL1A2 mutations. Fifteen (41 %) were novel mutations, and twelve (32 %) were familial mutations. A review of their medical records revealed that the 72 patients could be classified into OI type I (n = 42), III (n = 5), and IV (n = 25). Twenty-nine patients had helical mutations (caused by the substitution of a glycine within the Gly-X-Y triplet domain of the triple helix), and 42 had haploinsufficiency mutations (caused by frameshift, nonsense, and splice-site mutations). Compared with haploinsufficiency, the patients wit...
Osteogenesis Imperfecta: The Molecular Basis of Clinical Heterogeneity
Annals of the New York Academy of Sciences, 1988
During the last six years we have attempted to determine the molecular basis of osteogenesis irnperfecta (01) by analyzing the collagenous proteins synthesized by dermal fibroblasts cultured from affected individuals, their parents, and other family members. During that time we have studied members of more than 400 unrelated families, or, we estimate, between one and five percent of all families with 01 in the United States. These studies have, along with those from other laboratories (see REFS.
Annals of Human Genetics, 2020
Osteogenesis imperfecta (OI) is a group of inherited disorders with increased bone fragility and wide genetic heterogeneity. We report the outcome of clinical exome sequencing validated by Sanger sequencing in clinically diagnosed 54 OI patients in Indian population. In 52 patients, we report 20 new variants involving both dominant and recessive OI-specific genes and correlate these with phenotypes. COL1A1 and COL1A2 gene variants were identified in 44.23%, of which 28.84% were glycine substitution abnormalities. Two novel compound heterozygous variants in the FKBP10 gene were seen in two unrelated probands. A novel heterogeneous duplication of chromosomal region chr17: 48268168-48278884 from exons 1-33 of the COL1A1 gene was found in one proband. In five probands, there were additional variants in association with OI. These were ANO5 in association with CRTAP in two probands of the same family causing gnathodiaphyseal dysplasia, COL5A2 with LEPRE1 causing Ehlers Danlos syndrome, COL11A1 in addition to COL1A1 causing Stickler syndrome, and a previously unreported combination of SLC34A1 gene variant with FKBP10 leading to Fanconi renal tubular syndrome type II. Our findings demonstrate the efficacy of clinical exome sequencing in screening OI patients, classifying its subtypes, and identifying associated disorders in consanguineous populations. K E Y W O R D S brittle bones, clinical exome sequencing, genotype-phenotype, osteogenesis imperfecta 1 INTRODUCTION Osteogenesis imperfecta (OI) (MIM: 166200, 166210, 259420, and 166220) is a group of inherited disorders characterized by increased bone fragility, bone deformities, and decreased bone density (Van Dijk & Sillence, 2014). Manifestations vary from mild with a few fractures in the adolescent period, to severe with intrauterine fractures, stillbirths, and birth fractures (Sillence, Senn, & Danks, 1979). Other clinical features include dentinogenesis imperfecta (DI), blue sclerae, loss of hearing, short stature, and hyperlaxity. In rare cases, joint contractures, scoliosis, joint dislocations, and delayed motor development are also seen (Giri, Srivastava, Lallar, & Phadke, 2017). There is wide genetic heterogeneity in OI, with the involvement of up to 20 genes and another four
The present study aims to describe a large cohort of Italian patients affected by osteogenesis imperfecta, providing a picture of the clinical bony and non-bony features and the molecular background to improve knowledge of the disease to inform appropriate management in clinical practice. Methods: A total of 568 subjects (from 446 unrelated Italian families) affected by osteogenesis imperfecta who received outpatient care at Istituto Ortopedico Rizzoli from 2006 to 2021 were considered in the present study. Results: Skeletal and extraskeletal features were analyzed showing a lower height (mean z-scores equal to-1.54 for male patients and-1.47 for female patients) compared with the general Italian population. Half of the patient population showed one or more deformities, and most of the patients had suffered a relatively low number of fractures (<10). An alteration in the sclera color was identified in 447 patients. Similarly, several extraskeletal features, like deafness, dental abnormalities, and cardiac problems, were investigated. Additionally, inheritance and genetic background were evaluated, showing that most of the patients have a positive family history and the majority of pathogenic variants detected were on collagen genes, as per literature. Conclusion: This study supports the definition of a clear picture of the heterogeneous clinical manifestations leading to variable severity in terms of skeletal and extra-skeletal traits and of the genetic background of an Italian population of osteogenesis imperfecta patients. In this perspective, this clearly highlights the crucial role of standardized and structured collection of highquality data in disease registries particularly in rare disease scenarios, helping clinicians in disease monitoring and follow-up to improve clinical practice.