Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases

Celia L Gregson, Lawrie Wheeler, Sarah A Hardcastle, Louise H Appleton, Kathryn A Addison, Marieke Brugmans, Graeme R Clark, Kate A Ward, Margaret Paggiosi, Mike Stone, Joegi Thomas, Rohan Agarwal, Kenneth ES Poole, Eugene McCloskey, William D Fraser, Eleanor Williams, Alex N Bullock, George Davey Smith, Matthew A Brown, Jon H Tobias, Emma L Duncan

High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (e.g. LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. 258 unrelated HBM cases were identified from review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease (VBD) 52kb intronic deletion 3'). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C > T; p.Thr173Met], [c.796C > T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A > G; p.Asn198Ser], [c.724G > A; p.Ala242Thr], [c.266A > G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C > A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modelling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (∼3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance. This article is protected by copyright. All rights reserved.