Table 1.
Examples of monogenic metabolic bone disorders, modes of inheritance and genetic aetiology
| Mode of inheritance/Disease | Gene(s) | Chromosomal location | References |
|---|---|---|---|
| Autosomal dominant | |||
| Osteogenesis imperfecta (OI), types I‐IV | COL1A1, COL1A2 | 17q21.33, 7q21.3 | 20 |
| Osteogenesis imperfecta (OI), type V | IFITM5 | 11p15.5 | 23, 24 |
| Autosomal dominant hypophosphataemic rickets | FGF23 | 12p13.32 | 25 |
| Autosomal dominant high bone mass, type 1 | LRP5 | 11q13.2 | 47 |
| Autosomal dominant high bone mass, type 2 | LRP6 | 12p13.2 | 48 |
| Early‐onset osteoporosis | WNT1 | 12q13.12 | 19 |
| Familial hypocalciuric hypercalcaemia (FHH), types 1–3 | CASR, GNA11, AP2S1 | 3q21.1, 19p13.3, 19q13.3 | 31, 32, 33 |
| Autosomal dominant hypocalcaemia (ADH), types 1–2 | CASR, GNA11 | 3q21.1, 19p13.3 | 32, 37 |
| Familial expansile osteolysis | TNFRSF11A | 18q21.33 | 34, 35 |
| Hypophosphatasia | TNSALP/ALPL | 1p36.12 | 36 |
| Vitamin D‐dependent rickets, type 3 | CYP3A4 | 7q22.1 | 88 |
| Pseudohypoparathyroidism, type 1a (PHP1a) a | GNAS | 20q13.3 | 39 |
| Pseudopseudohypoparathyroidism (PPHP) a | GNAS | 20q13.3 | 39 |
| Pseudohypoparathyroidism, type 1b (PHP1b) a | GNAS, NESP55, STX16 | 20q13.3 | 39 |
| Autosomal recessive | |||
| Osteogenesis imperfecta (OI), type VI | SERPINF1 | 17p13.3 | 106 |
| Osteogenesis imperfecta (OI), type VII | CRTAP | 3p22.3 | 21 |
| Osteogenesis imperfecta (OI), type VIII | P3H1/LEPRE1 | 1p34.2 | 107 |
| Osteogenesis imperfecta (OI), type XV | WNT1 | 12q13.12 | 19 |
| Hypophosphatasia | TNSALP/ALPL | 1p36.12 | 36 |
| Neonatal severe hyperparathyroidism (NSHPT) | CASR | 3q21.1 | 31 |
| Vitamin D‐dependent rickets, type 1 | CYP27B1 | 12q14.1 | 10 |
| Vitamin D‐dependent rickets, type 2 | VDR | 12q13.11 | 10 |
| Autosomal recessive hypophosphataemic rickets | DMP1, ENPP1 | 4q22.1, 6q23.2 | 27, 28 |
| Hereditary hypophosphataemic rickets with hypercalciuria | SLC34A3 | 9q34.3 | 29, 30 |
| Osteoporosis‐pseudoglioma syndrome | LRP5 | 11q13.2 | 46 |
| Sclerosteosis, type 1 | SOST | 17q21.31 | 49 |
| Sclerosteosis, type 2 | LRP4 | 11p11.2 | 50 |
| Pyle's disease | SFRP4 | 7p14.1 | 54 |
| Juvenile Paget disease | TNFRSF11B | 8q24.12 | 108 |
| X‐linked dominant | |||
| X‐linked hypophosphatemic (XLH) rickets | PHEX | Xp22.11 | 26 |
| X‐linked recessive | |||
| X‐linked osteoporosis | PLS3 | Xq23 | 18 |
| Dent disease, type 1 | CLCN5 | Xp11.23 | 11 |
| Mitochondrial | |||
| Mitochondrial encephalomyopathy with lactic acidosis and stoke‐like episodes (MELAS) | Mitochondrial genome | ‐ | 13 |
| Kearns‐Sayre syndrome | Mitochondrial genome | ‐ | 14 |
| Mosaicism | |||
| McCune‐Albright syndrome (polyostotic fibrous dysplasia) a | GNAS | 20q13.3 | 15 |
| Osteogenesis imperfecta (OI) b | COL1A1/COL1A2 | 17q21.33, 7q21.3 | |
a
Parentally imprinted
b
Autosomal disorder manifesting as post‐zygotic somatic mosaicism in the developing fetus, or arising from germline mosaicism in an apparently unaffected parent