Introduction to genetics of skeletal and mineral metabolic diseases

Many skeletal and mineral metabolic diseases have a genetic basis, which may reflect a germline single gene abnormality (i.e., a monogenic or Mendelian disorder), a somatic single gene defect (i.e., a postzygotic mosaic disorder), or several genetic variants (i.e., oligogenic or polygenic disorders). Pathogenic germline variants causing monogenic diseases usually have a large effect (i.e., penetrance), whereas oligogenic or polygenic disorders summate several genetic variations, each of which may have a small effect with greater or smaller contributions from environmental factors (i.e., multifactorial disorders). In addition, most monogenic disorders result from rare pathogenic variants affecting the coding sequence of the responsible gene, while most genetic variants underlying polygenic traits are within noncoding regions, typically near candidate genes implicated in the respective phenotype. However, there is considerable overlap among the genes contributing to polygenic and monogenic skeletal disorders. Recognition of these disorders is important for understanding the recurrence risk and often for identifying affected family members. Rapid advances in DNA sequencing technology over the past 20 years have greatly expanded the genetic taxonomy of heritable skeletal and mineral metabolic diseases such that clinical genetic testing is now an important component of the diagnostic pathways for the many and varied presentations. Therefore it is important that clinicians appreciate the range of genetic testing to ensure appropriate use and interpretation. These considerations are reviewed in this chapter.