IllnessOsteoporosis, monogenic; differential diagnosis

NGS + SNP

With the exception of very few monogenic diseases (e.g. primary LRP5 osteoporosis, osteoporosis transitional forms in osteogenesis imperfecta etc.), the complex etiology of osteoporosis is generally influenced by environmental factors (diet, ethnicity, age etc.). As a multifactorial polygenic disease, genetic determinants are modulated by hormonal, environmental, and nutritional factors. Typically, two forms of common osteoporosis are distinguished: osteoporosis associated with estrogen deficiency at menopause in women and osteoporosis associated with calcium deficiency and skeletal aging, especially in the elderly. Because many environmental factors influence bone density, the heritability of bone density in the spine and hip is estimated to be 70-85%. Susceptibility to osteoporosis also has a strong genetic component, with genes accounting for approximately 25% of the variance in susceptibility to osteoporotic fractures. Multiple genes interact in complex ways with each other as well as with environmental influences. Inconspicuous genetic findings are the rule for the vast majority of cases of estrogen deficiency and skeletal aging. The rare monogenic entities are inherited in an autosomal dominant or recessive manner.

References: https://asbmr.onlinelibrary.wiley.com/doi/full/10.1359/JBMR.050101

https://www.frontiersin.org/articles/10.3389/fendo.2019.00070/full

https://genomebiology.biomedcentral.com/articles/10.1186/s13059-020-01997-2

• Alias: LRP5-related primary osteoporosis
• Allelic: Caffey disease (COL1A1)
• Allelic: Combined osteogenesis imperfecta + Ehlers-Danlos syndrome 1 (COL1A1)
• Allelic: Combined osteogenesis imperfecta + Ehlers-Danlos syndrome 2 (COL1A2)
• Allelic: Ehlers-Danlos syndrome, arthrochalasia type, 1 (COL1A1)
• Allelic: Ehlers-Danlos syndrome, arthrochalasia type, 2 (COL1A2)
• Allelic: Ehlers-Danlos syndrome, cardiac valvular type (COL1A2)
• Allelic: Exudative vitreoretinopathy 4 (LRP5)
• Allelic: Fanconi renotubular syndrome 2 (SLC34A1)
• Allelic: Hypercalcemia, infantile, 2 (SLC34A1)
• Allelic: Hyperostosis, endosteal (LRP5)
• Allelic: IFAP syndrome with or without BRESHECK syndrome (MBTPS2)
• Allelic: Keratosis follicularis spinulosa decalvans, XL (MBTPS2)
• Allelic: Olmsted syndrome, XL (MBTPS2)
• Allelic: Osteogenesis imperfecta, type I (COL1A1)
• Allelic: Osteogenesis imperfecta, type II (COL1A1, COL1A2)
• Allelic: Osteogenesis imperfecta, type III (COL1A1, COL1A2)
• Allelic: Osteogenesis imperfecta, type IV (COL1A1, COL1A2)
• Allelic: Osteogenesis imperfecta, type XII (SP7)
• Allelic: Osteogenesis imperfecta, type XV (WNT1)
• Allelic: Osteopetrosis, AR 2 (TNFSF11)
• Allelic: Osteopetrosis, AR 7 (TNFRSF11A)
• Allelic: Osteosclerosis (LRP5)
• Allelic: Paget disease of bone 2, early-onset (TNFRSF11A)
• Allelic: Paget disease of bone 5, juvenile-onset (TNFRSF11B)
• Allelic: Polycystic liver disease 4 with/-out kidney cysts (LRP5)
• Allelic: Preterm premature rupture of the membranes, susceptibility to (SERPINH1)
• Allelic: Tumoral calcinosis, hyperphosphatemic, familial, 2 (FGF23)
• Allelic: van Buchem disease, type 2 (LRP5)
• Allelic; Osteopetrosis, AD 1 (LRP5)
• Bone mineral density QTL18, osteoporosis (PLS3)
• Bone mineral density variability 1 (LRP5)
• Bruck syndrome 1 (FKBP10)
• Bruck syndrome 2 (PLOD2)
• Craniodiaphyseal dysplasia, AD (SOST)
• Hypophosphatemic rickets, AD (FGF23)
• Idiopathic juvenile osteoporosis [1 case - no gene/no locus]
• Juvenile osteoporosis, osteopenia, osteoporosis, recurrent fractures [panelapp] (COPB2)
• Nephrolithiasis/osteoporosis, hypophosphatemic, 1 (SLC34A1)
• Osteogenesis imperfecta + decreased bone density [panelapp] (COL1A1, -2, CRTAP, PPIB)
• Osteogenesis imperfecta, type IX (PPIB)
• Osteogenesis imperfecta, type V (IFITM5)
• Osteogenesis imperfecta, type VI (SERPINF1)
• Osteogenesis imperfecta, type VII (CRTAB)
• Osteogenesis imperfecta, type VIII (P3H1)
• Osteogenesis imperfecta, type X (SERPINH1)
• Osteogenesis imperfecta, type XI (FKBP10)
• Osteogenesis imperfecta, type XIII (BMP1)
• Osteogenesis imperfecta, type XIV (TMEM38B)
• Osteogenesis imperfecta, type XIX (MBTPS2)
• Osteogenesis imperfecta, type XV (WNT1)
• Osteogenesis imperfecta, type XVI (CREB3L1)
• Osteogenesis imperfecta, type XVII (SPARC)
• Osteogenesis imperfecta, type XVIII (FAM46A)
• Osteogenesis imperfecta/osteoporosis [panelapp] (SERPINF1)
• Osteolysis, familial expansile (TNFRSF11A)
• Osteoporosis [panelapp] (LRP5)
• Osteoporosis association [Lit.] (AXIN1, CTNNB1, DKK1, IBSP, ITGA1, ITGB3, JAG1, LRP6, MEF2C, PTHLH)
• Osteoporosis association [Lit.] (RUNX2, SOX9, SPP1, TNFSF11, WNT16, WNT4, WNT5B)
• Osteoporosis, early-onset, susceptibility to, AD (WNT1)
• Osteoporosis-pseudoglioma syndrome (LRP5)
• Rickets, vitamin D-resistant, type IIA (VDR)
• Sclerosteosis 1 (SOST)
• Susceptibility [OMIM]: Bone mineral density variation QTL, osteoporosis (COL1A1)
• Susceptibility [OMIM]: Osteoporosis (BMND7)
• Susceptibility [OMIM]: Osteoporosis (BMND8)
• Susceptibility [OMIM]: Osteoporosis, postmenopausal (COL1A2)
• Susceptibility [OMIM]: Osteoporosis, postmenopausal, susceptibility (CALCR)
• Susceptibility [OMIM]: Osteoporosis, susceptibility to (PDLIM4)
• XL osteoporosis + fractures [panelapp] (PLS3)