A cohort of children presenting with increased bone fragility and no extraskeletal signs of osteogenesis imperfecta tended to have a collection of common gene variants that predispose to osteoporotic fracture rather than a monogenic etiology of their condition, according to findings published in the Journal of Bone and Mineral Research.
J. Brent Richards
“These findings imply that an important proportion of patients with apparent monogenic Mendelian disease and a significant fracture history in childhood and suspicion of osteogenesis imperfecta could have an increased burden of common risk alleles predisposing them to this clinical presentation,” J. Brent Richards, MD, MSc, professor of medicine at Jewish General Hospital in Montreal, and colleagues wrote. “These results may have clinical implications, since they imply that polygenic predisposition to disease may be present in an important proportion of individuals who are presumed to have Mendelian forms of disease.”
Richards and colleagues analyzed data from children with significant fracture history but no typical osteogenesis imperfecta phenotype participating in three separate cohorts (n = 131), as well as a control population from the UK Biobank, a population-based health study (n = 80,027). A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of whom 68 had a negative osteogenesis imperfecta gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among whom 18 had a negative osteogenesis imperfecta gene panel. All children underwent DXA measurements to assess lumbar spine areal bone mineral density, transferred to age- and sex-specific z scores.
A cohort of children presenting with increased bone fragility and no extraskeletal signs of osteogenesis imperfecta tended to have a collection of common gene variants that predispose to osteoporotic fracture rather than a monogenic etiology of their condition.
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Researchers generated a polygenic score of heel ultrasound-derived speed of sound, which predicts risk for osteoporotic fracture, and tested whether children with fracture history had lower heel ultrasound-derived speed of sound compared with controls.
The average heel ultrasound-derived speed of sound across the three cohorts was –0.47 standard deviation (SD) lower vs. controls than that in the UK Biobank (P = 1.1 x 10-5). In sensitivity analyses for a subset of 78 children suspected of monogenic disease who underwent gene sequencing, the heel ultrasound-derived speed of sound was lower (–0.76 SD; P =5.3 x 10-10). Among children with fracture history, researchers observed eight participants (6%) with a heel ultrasound-derived speed of sound that was –2 SD from the mean; their mean lumbar spine DXA-derived BMD z score was –1.7.
“As our ability to quantify polygenic risk improves through rapidly evolving polygenic risk scores, the ability to estimate this risk may inform clinical care not only of fracture, but of other traits and diseases, such as extreme presentations of autism, obesity and short or tall stature, which appear to have both monogenic and polygenic forms of the disease,” the researchers wrote. “The accuracy of polygenic risk scores depend in large part on the sample size from which they are calculated, suggesting that further increases in sample sizes of genome-wide genotyped populations will help to improve their clinical performance and allow the establishment of clinically relevant cutoffs for risk stratification. In the absence of such cutoffs, polygenic risk scores, although not deterministic, can still be informative and complement other approaches, such as disease-specific gene panel sequencing, whole exome or genome sequencing.” – by Regina Schaffer
Disclosures: The authors report no relevant financial disclosures.