Osteoporosis is usually considered a polygenic disease. Osteogenesis imperfecta (OI) is a group of monogenic disorders of bone fragility, due to dominant or recessive mutations of large effect, with 23 genes identified to date for OI and related conditions. It is not known whether individuals with idiopathic osteoporosis carry deleterious variants in OI genes.

Whole-exome sequencing was performed in 500 Caucasian women aged 55-80 years with low bone mineral density (t-score −1.5 to −4 at total hip) recruited as part of the Anglo-Australian Osteoporosis Consortium. Data were analysed for rare (minor allele frequency (MAF) <0.001) variants of potentially damaging consequence in known OI genes (BMP1, COL1A1, COL1A2, CREB3L1, CRTAP, FKBP10, IFITM5, LEPRE1, LRP5, MBTPS2, P3H1, P4HB, PLOD2, PLS3, PPIB, SEC24D, SERPINF1, SERPINH1, SP7, SPARC, TMEM38B, WNT1, XYLT2). Variants were considered likely pathogenic if the variant, or one in a neighbouring base, had been reported in OI previously; or were novel variants predicted to be damaging affecting highly evolutionarily conserved base/s (similar variants with MAF 0.001 were considered suggestive, as were splice site variants).

18 individuals had heterozygous variants in COL1A1 or COL1A2. One individual had a highly suggestive variant in WNT1. Three individuals had LRP5 variants previously reported in osteoporosis-pseudoglioma. An additional five individuals had novel or rare variants in highly conserved bases in LRP5 not seen in a high bone mass control cohort. Four individuals had variants in IFITM5 although not the mutation reported for OI type 5; no information was available regarding interosseous membrane calcification.

Variants in known OI genes are observed frequently in OI cases. Genetic screening can now form part of the investigation for severe and/or idiopathic osteoporosis.

Table 1