Current Practices and the Provider Perspectives on Inconclusive Genetic Test Results for Osteogenesis Imperfecta in Children with Unexplained Fractures: ELSI Implications

Abstract

Genetic testing can be used to determine if unexplained fractures in children could have resulted from a predisposition to bone fractures, e.g., osteogenesis imperfecta. However, uncertainty is introduced if a variant of unknown significance (VUS) is identified. Proper interpretation of VUS in these situations is critical because of its influence on clinical care and in court rulings. This study sought to understand how VUS are interpreted and used by practitioners when there is a differential diagnosis including both osteogenesis imperfecta and non-accidental injury.

A 15-question survey was emailed to physicians who requested analysis of two genes, COL1A1 and COL1A2, from the University of Washington from 2005-2013 for patient cases involving suspicion of child abuse.

Among the 89 participants, responses differed about when genetic testing should be ordered for osteogenesis imperfecta, who should be consulted about utilization of VUS test results, follow-up procedures, and who should receive the VUS results.

There are no clear guidelines for how to interpret and follow up on VUS. In the legal setting, misinterpreted VUS could lead to unintended consequences and deleterious ramifications for family members. The need for better practice guidelines to help promote more equitable handling of these sensitive legal cases is clear.

Get full access to this article

View all access options for this article.

References

T. D.

Wardinsky

, “Genetic and Congenital Defect Conditions That Mimic Child Abuse,” Journal of Family Practice 41, no. 4 (1995): 377–383.

D. O.

Sillence ,

Senn , and

D. M.

Danks , “Genetic Heterogeneity in Osteogenesis Imperfecta,” Journal of Medical Genetics 16, no. 2 (1979): 101–116.

Marlowe ,

M. G.

Pepin , and

P. H.

Byers , “Testing for Osteo-genesis Imperfecta in Cases of Suspected Non-accidental Injury,” Journal of Medical Genetics 39, no. 6 (2002): 382–386.

J. M.

Leventhal ,

K. D.

Martin , and

A. G.

Asnes , “Incidence of Fractures Attributable to Abuse in Young Hospitalized Children: Results from Analysis of a United States Database,” Pediatrics 122, no. 3 (2008): 599–604.

See Leventhal, supra note 4.

See Marlowe, supra note 3.

B. T.

Tinkle and

R. J.

Wenstrup , “A Genetic Approach to Fracture Epidemiology in Childhood,” American Journal of Medical Genetics Part C: Seminars in Medical Genetics 139c., no. 1 (2005): 38–54.

University of Leicester, “Osteogenesis Imperfecta & Ehlers-Danlos Syndrome Variant Databases,” available at <http://www.le.ac.uk/ge/collagen/> (last visisted July 18, 2016); R. Dalgleish, “The Human Type I Collagen Mutation Database,” Nucleic Acids Research 25 (1997): 181-187; R. Dalgleish, “The Human Collagen Mutation Database,” Nucleic Acids Research 26 (1998): 253–255.

E. R.

Valadares ,

T. B.

Carneiro ,

P. M.

Santos ,

A. C.

Oliveira , and

Zabel , “What Is New in Genetics and Osteogenesis Imperfecta Classification?” Journal of Pediatrics (Rio J) 90, no. 6 (2014): 536–541.

10.

F. S.

van Dijk ,

P. H.

Byers ,

Dalgleish ,

Malfait ,

Maugeri , and

Rohrbach et al., “EMQN Best Practice Guidelines for the Laboratory Diagnosis of Osteogenesis Imperfecta,” European Journal of Human Genetics 20, no. 1 (2012): 11–19.

11.

Proost ,

Vandeweyer ,

J. A.

Meester ,

Salemink ,

Kempers , and

Ingram et al., “Performant Mutation Identification using Targeted Next Generation Sequencing of Fourteen Thoracic Aortic Aneurysm Genes,” Human Mutations 36, no. 8 (2015): 808-814; W. Wooderchak-Donahue, C. VanSant-Webb, T. Tvrdik, P. Plant, T. Lewis, and J. Stocks et al., “Clinical Utility of a Next Generation Sequencing Panel Assay for Marfan and Marfan-Like Syndromes Featuring Aortopathy,” American Journal of Medical Genetics-Part A 167A no. 8 (2015): 1747–1757.

12.

Matter of Maria S. (Samantha S.) Decided April 29, 2014. NY Slip Op 50690(U), New York State Law Reporting Bureau pursuant to Judiciary Law § 431 Justia Law, available at <http://law.justia.com/cases/new-york/other-courts/2014/2014-ny-slip-op-50690-u.html> (last visited July 18, 2016).

13.

See Marlowe et al., supra note 3.

14.

H. F.

Hsieh , and

S. E.

Shannon , “Three Approaches to Qualitative Content Analysis,” Qualitative Health Research 15 (2005): 1277–1288.

15.

American Society of Human Genetics (ASHG) Member Directory Search, available at <http://www.ashg.org/pages/member_search.shtml> (last visted July 18, 2016).

16.

Snyder and the American College of Physicians Ethics, Professionalism, and Human Rights Committee, “American College of Physicians Ethics Manual, 6th Edition,” Annals of Internal Medicine 156 (2012): 73–104.