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© 2018 Elsevier Inc. All rights reserved. Many skeletal and mineral metabolic diseases have a genetic basis, which may be a germline single gene abnormality (i.e., a monogenic or Mendelian disorder), a somatic single gene defect (i.e., a postzygotic mosaic disorder), or involve several genetic variants (i.e., oligogenic or polygenic disorders). Genetic mutations causing Mendelian diseases usually have a large effect (i.e., penetrance), whereas oligogenic or polygenic disorders are associated with several genetic variations, each of which may have small effects with greater or smaller contributions from environmental factors (i.e., multifactorial disorders). Recognition of monogenic hereditary disorders is of clinical importance, as it may lead to relevant and timely investigations with correct treatment for the patient, and the patient's relatives. The diagnosis of monogenic skeletal disease requires an awareness of the great diversity of symptoms and signs that may be associated with the disorder and, as ever, clinical skill is required. Thus, the clinician will need to pursue a careful and systematic approach with detailed history and physical examination and appropriate laboratory evaluations that should lead to judicious use of the range of diagnostic tools available. Finally, the clinician will require an appreciation of the increasing number and complexity of molecular genetic tests available to ensure their appropriate use and interpretation. These considerations are reviewed in this chapter.

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