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Archives of Osteoporosis

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01-12-2021 | Osteogenesis Imperfecta | Short Communication

Diagnostic utility of next-generation sequence genetic panel testing in children presenting with a clinically significant fracture history

Authors: Jennifer Harrington, Abdulmajeed AlSubaihin, Lucie Dupuis, Peter Kannu, Roberto Mendoza-Londono, Andrew Howard

Published in: Archives of Osteoporosis | Issue 1/2021

Abstract

Summary

We assessed the diagnostic utility of genetic panel testing to detect pathogenic variants associated with osteogenesis imperfecta in children presenting with multiple fractures. Thirty-five percent of children had a pathogenic variant. A history of a femur fracture or a first fracture occurring under 2 years of age were significant clinical predictors.

Purpose

The use of next-generation sequencing (NGS) genetic panels offers a comprehensive rapid diagnostic test to evaluate for pathogenic variants in the expanding list of genes associated with osteogenesis imperfecta (OI). We aimed to assess the diagnostic utility of this method in children with a clinically significant fracture history.

Methods

NGS panel testing was performed in 87 children presenting with multiple long bone or vertebral fractures. Subjects with a known family history of OI were excluded. Associations between genetic findings and clinical characteristics were analyzed in a retrospective observational study.

Results

Thirty-five percent of patients were found to have a disease-causing variant, with a higher detection rate in those patients with extra-skeletal features of OI (94 vs. 20%, p < 0.001). In subjects with extra-skeletal clinical OI features, 69% were found to have pathogenic variants in COL1A1 or COL1A2. In children without extra-skeletal features, 14 of 70 (20%) had pathogenic variants, of which 7 were variants in type 1 collagen, and the remaining 7 variants were associated with osteoblast function or signaling (PLS3, SP7, LRP5). Clinical predictors for detecting a disease-causing variant included a history of having a first fracture that occurred under 2 years of age (Odds ratio 5.5, 95%CI 1.8, 16.9) and a history of a femur fracture (Odds ratio 3.3, 95%CI 1.0, 11.1).

Conclusion

NGS panel testing will detect causative pathogenic variants in up to a third of children with a clinically significant fracture history, particularly where there is a history of early femur fracture.

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Hedstrom EM, Svensson O, Bergstrom U, Michno P (2010) Epidemiology of fractures in children and adolescents. Acta Orthop 81(1):148–153. https://doi.org/10.3109/17453671003628780CrossRefPubMedPubMedCentral

Cooper C, Dennison EM, Leufkens HG, Bishop N, van Staa TP (2004) Epidemiology of childhood fractures in Britain: a study using the general practice research database. J Bone Miner Res 19(12):1976–1981. https://doi.org/10.1359/JBMR.040902CrossRefPubMed

Jones IE, Williams SM, Dow N, Goulding A (2002) How many children remain fracture-free during growth? a longitudinal study of children and adolescents participating in the Dunedin Multidisciplinary Health and Development Study. Osteoporos Int 13(12):990–995. https://doi.org/10.1007/s001980200137CrossRefPubMed

Harrington J, Sochett E (2015) The Child with Multiple Fractures, What Next? Pediatr Clin North Am 62(4):841–855. https://doi.org/10.1016/j.pcl.2015.04.006CrossRefPubMed

Stevenson DA, Carey JC, Byrne JL, Srisukhumbowornchai S, Feldkamp ML (2012) Analysis of skeletal dysplasias in the Utah population. Am J Med Genet A 158A(5):1046–1054. https://doi.org/10.1002/ajmg.a.35327CrossRefPubMed

Stoll C, Dott B, Roth MP, Alembik Y (1989) Birth prevalence rates of skeletal dysplasias. Clin Genet 35(2):88–92CrossRefPubMed

Marini JC, Forlino A, Bachinger HP, Bishop NJ, Byers PH, Paepe A, Fassier F, Fratzl-Zelman N, Kozloff KM, Krakow D, Montpetit K, Semler O (2017) Osteogenesis imperfecta. Nat Rev Dis Primers 3:17052. https://doi.org/10.1038/nrdp.2017.52CrossRefPubMed

Bishop N, Arundel P, Clark E, Dimitri P, Farr J, Jones G, Makitie O, Munns CF, Shaw N, International Society of Clinical D (2014) Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2013 Pediatric Official Positions. J Clin Densitom 17(2):275–280. https://doi.org/10.1016/j.jocd.2014.01.004CrossRefPubMed

Dietitians of Canada (2014) WHO Growth Charts for Canada. www.whogrowthcharts.ca. Accessed 11 Jan 2020

10.

Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8(9):1137–1148. https://doi.org/10.1002/jbmr.5650080915CrossRefPubMed

11.

Zemel BS, Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA, Frederick MM, Huang X, Lu M, Mahboubi S, Hangartner T, Winer KK (2011) Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab 96(10):3160–3169. https://doi.org/10.1210/jc.2011-1111CrossRefPubMedPubMedCentral

12.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30CrossRefPubMedPubMedCentral

13.

Bardai G, Ward LM, Trejo P, Moffatt P, Glorieux FH, Rauch F (2017) Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta. Osteoporos Int 28(7):2095–2101. https://doi.org/10.1007/s00198-017-4031-2CrossRefPubMed

14.

Moon RJ, Harvey NC, Curtis EM, de Vries F, van Staa T, Cooper C (2016) Ethnic and geographic variations in the epidemiology of childhood fractures in the United Kingdom. Bone 85:9–14. https://doi.org/10.1016/j.bone.2016.01.015CrossRefPubMedPubMedCentral

15.

Mayranpaa MK, Makitie O, Kallio PE (2010) Decreasing incidence and changing pattern of childhood fractures: A population-based study. J Bone Miner Res 25(12):2752–2759. https://doi.org/10.1002/jbmr.155CrossRefPubMed

16.

Ward LM, Weber DR, Munns CF, Hogler W, Zemel BS (2020) A Contemporary View of the Definition and Diagnosis of Osteoporosis in Children and Adolescents. J Clin Endocrinol Metab 105 (5). https://doi.org/10.1210/clinem/dgz294

17.

Bardai G, Moffatt P, Glorieux FH, Rauch F (2016) DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos Int 27(12):3607–3613. https://doi.org/10.1007/s00198-016-3709-1CrossRefPubMed

18.

Liu Y, Asan MD, Lv F, Xu X, Wang J, Xia W, Jiang Y, Wang O, Xing X, Yu W, Wang J, Sun J, Song L, Zhu Y, Yang H, Wang J, Li M (2017) Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing. Osteoporos Int 28(10):2985–2995. https://doi.org/10.1007/s00198-017-4143-8CrossRefPubMed

Title: Diagnostic utility of next-generation sequence genetic panel testing in children presenting with a clinically significant fracture history
Authors: Jennifer Harrington
Abdulmajeed AlSubaihin
Lucie Dupuis
Peter Kannu
Roberto Mendoza-Londono
Andrew Howard
Publication date: 01-12-2021
Publisher: Springer London
Keyword: Osteogenesis Imperfecta
Published in: Archives of Osteoporosis / Issue 1/2021
Print ISSN: 1862-3522
Electronic ISSN: 1862-3514
DOI: https://doi.org/10.1007/s11657-021-00943-4

At a glance: The STEP trials

Springer Medicine

Diagnostic utility of next-generation sequence genetic panel testing in children presenting with a clinically significant fracture history

Abstract

Summary

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Summary

Purpose

Methods

Results

Conclusion

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