Introduction to genetics of skeletal and mineral metabolic diseases

TY - CHAP

T1 - Introduction to genetics of skeletal and mineral metabolic diseases

AU - Newey, Paul J.

AU - Lovegrove, Catherine E.

AU - Howles, Sarah A.

AU - Whyte, Michael P.

AU - Thakker, Rajesh V.

N1 - Publisher Copyright: © 2026 Elsevier Inc. All rights reserved.

PY - 2026/3/30

Y1 - 2026/3/30

N2 - 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.

AB - 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.

KW - DNA sequencing

KW - genetic testing

KW - Monogenic

KW - pathogenic variant

KW - variant interpretation

UR - https://www.scopus.com/pages/publications/105036918340

U2 - 10.1016/B978-0-443-13683-2.00015-3

DO - 10.1016/B978-0-443-13683-2.00015-3

M3 - Chapter

AN - SCOPUS:105036918340

SN - 9780443136849

SP - 3

EP - 28

BT - Genetics of Bone Biology and Skeletal Disease

A2 - Thakker, Rajesh V

A2 - Whyte, Michael P

A2 - Eisman, John A

A2 - Igarashi, Takashi

PB - Elsevier

CY - London

ER -