Bone Abstracts

Objectives: To evaluate the diagnostic outcomes of massively parallel sequencing (MPS) and identify genotype-phenotype correlations in children and adolescents with recurrent fractures.

Methods: A retrospective chart audit was conducted of children and adolescents referred to the endocrine clinic at a tertiary children’s referral hospital with a history of recurrent fractures. Phenotypic data including fracture history, bone mineral density (BMD) and biochemistry for bone/mineral homeostasis were collected. MPS for a brittle bone panel of 13 genes was also undertaken. Statistical analysis was performed using SPSS software to determine a correlation between genotype and phenotypic variables.

Results: The study population comprised 83 individuals. Of these, 24 (29%) were noted to have clinically diagnostic features of OI and were characterised as a separate group for analysis. Out of the 59 remaining patients, 36 (61%) had normal genetic testing, 17 (29%) had a variant of unknown significance (VOUS), 5 (8%) were heterozygous for pathogenic LRP5 mutations and 1 (2%) had a pathogenic COL1A2 mutation. VOUS were identified in COL1A1, FKBP10, PLOD2, LRP5, CRTAP, SERPINH1, SERPINF1, and P3H1. There was no correlation between positive mutation detection and type of fracture, number of fractures or BMD variables.

Conclusion: There was no significant correlation between MPS result and patient phenotype in those without a clinical diagnosis of OI. Although the diagnostic yield of MPS from those without clinical features of OI was low, there remain a significant number of identified mutations in this group suggesting a low threshold for genetic testing. Functional studies are underway to determine the pathogenicity of the large number of VOUS detected by MPS. These data may help elucidate which children would benefit from molecular genetic testing.

Disclosure: The authors declared no competing interests.