The Polygenic and Monogenic Basis of Paediatric Fractures

Abstract

Purpose of Review Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped by the individual genetic background influencing the acquisition of bone mineral density, and therefore, the skeletal fragility as shown in adults. Here, we examine paediatric fractures from the perspective of monogenic and complex trait genetics. Recent Findings Large-scale genome-wide studies in children have identified ~44 genetic loci associated with fracture or bone traits whereas ~35 monogenic diseases characterized by paediatric fractures have been described. Summary Genetic variation can predispose to paediatric fractures through monogenic risk variants with a large effect and polygenic risk involving many variants of small effects. Studying genetic factors influencing peak bone attainment might help in identifying individuals at higher risk of developing early-onset osteoporosis and discovering drug targets to be used as bone restorative pharmacotherapies to prevent, or even reverse, bone loss later in life.

Early-Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen

“…(22) Recently, the phenotypic and genetic spectrum of OI has considerably expanded and pathogenic variants in at least 16 other genes have been identified. (23,24) Most of these genes play a pivotal role in synthesis, posttranslational modification, and processing of type I collagen. (22,23,25,26) This heterogeneity in disease spectrum has complicated the disease classification and has led to challenges in defining each clinical entity in the Online Mendelian Inheritance in Man (OMIM) catalogue.…”

“…For example, osteoporosis-pseudoglioma syndrome (OPPG, MIM 259770) and spondylo-ocular syndrome (MIM 605822) are both characterized by severe childhood-onset skeletal fragility and ocular manifestations. (23,24) Further, various mineralization defects, such as hypophosphatasia (HPP) due to pathogenic variants in the gene encoding tissue-nonspecific alkaline phosphatase (ALPL), (27) or various inherited forms of hypophosphatemia, due to defective renal phosphate handling, lead to skeletal fragility.…”

Medical Care Use Among Patients with Monogenic Osteoporosis Due to Rare Variants in LRP5, PLS3, or WNT1

“…Due to the wide implementation of next generation sequencing, several monogenic defects causing early-onset osteoporosis have been identified in recent years [ 3 , 4 ]. This study focuses primarily on pathogenic or rare suspicious variants in low-density lipoprotein receptor-related protein 5 (LRP5) , plastin 3 ( PLS3) , or proto-oncogene Wnt-1 ( WNT1) as monogenic causes of osteoporosis [ 5 ].…”