COL1A1 and COL1A2 sequencing results in cohort of patients undergoing evaluation for potential child abuse

Abstract

Child abuse is a major public health concern that can explain a proportion of fractures in children. Osteogenesis imperfecta (OI) is the most common inherited syndrome that predisposes to skeletal fractures. We conducted a retrospective analysis of data from clinical, laboratory, and radiographic information from children evaluated for child abuse in which molecular testing for COL1A1 and COL1A2 genes was conducted. A total of 43 patients underwent molecular testing for OI. Pathogenic variants predicted to result in a mild form of OI were found in two patients (5%), both clinically suspected to have this diagnosis. None of the cases in whom OI molecular testing was ordered when maltreatment concerns were thought to be more likely (0/35) were identified to have pathogenic variants. After reviewing each individual case, the final diagnosis was child abuse for 34 cases (77%), and additional radiographic and laboratory studies did not identify any with inherited metabolic predisposition to fracture or rickets. We conclude that routine testing for OI in the setting of child abuse when no other suggestive clinical findings are present has a low yield. A careful review of the medical history and a detailed clinical evaluation help identify those at risk for genetic alterations. © 2016 Wiley Periodicals, Inc.

Características Clínicas E Padrão De Fraturas No Momento Do Diagnóstico De Osteogênese Imperfeita Em Crianças

“…Parents of children with OI often deal with the suspicion of CPA, by health teams during the initial treatment of fractures before the diagnosis is established 27 28 , 29 , 30 However, OI and CPA are not mutually exclusive 28 …”

“…Zarate et al suggested, in cases suspected of CPA and OI, to consider genetic testing only in the presence of clinical features of OI, or in cases with a family history of the disorder 29 . However, in cases of suspected nonaccidental injury, with unexplained fractures in children under investigation for OI, Pepin and Byers suggested evaluating the need for molecular analysis in some cases, considering that the clinical features of the disorder may not be observed during the clinical investigation 30 …”

Interpreting Osteogenesis Imperfecta Variants of Uncertain Significance in the Context of Physical Abuse: A Case Series

“…28 Given reports of potential nonosseous findings and additional bone findings over time, it is important to evaluate the totality of the context of a case using information gathered from a multidisciplinary team when evaluating the etiology and significance of fractures for potential physical abuse. 8 One can neither exclude underlying bone disease merely on the basis of nonskeletal findings nor exclude abuse based solely on the presence of a VUS, even if the variant is determined to be clinically significant.…”

“…1 While few unsuspected cases are found, genetic testing for OI and other metabolic diseases of bone are common in the workup of potential child physical abuse involving fractures to assure consideration of all possible causes. [2][3][4][5][6][7][8] During the course of genetic testing, patients may have test results reported as "variants of unknown significance" (VUS) which are "sequence variants of uncertain pathogenicity in genes known to cause inherited Mendelian diseases in which molecular genetic testing has a proven clinical validity and utility." 9,10 VUS are identified with recognition that the clinical significance of any given sequence variant falls along a gradient, ranging from those in which the variant is pathogenic, likely pathogenic, likely benign, or benign.…”

A fracture, a family, legal entanglement, expensive investigation, and a familiar disease

“…Most pathogenic variants in COL1A1 are sporadic. 5 , 6 Because of the potential for mosaicism in an unaffected parent, variant-specific testing of the parents of AA was made available to help determine if the variant was inherited or arose de novo; in addition, this will provide information required for accurate genetic counseling for this family. Parents did not complete testing as of time of writing; if neither parent is found to carry the G224V variant in the COL1A1 gene, the possibility of mosaicism cannot be excluded, and offspring of either parent may be at risk of carrying this variant.…”