Genetics of monogenic disorders of calcium and bone metabolism

Abstract

Disorders of calcium homeostasis are the most frequent metabolic bone and mineral disease encountered by endocrinologists. These disorders usually manifest as primary hyperparathyroidism (PHPT) or hypoparathyroidism (HP), which have a monogenic aetiology in 5%–10% of cases, and may occur as an isolated endocrinopathy, or as part of a complex syndrome. The recognition and diagnosis of these disorders is important to facilitate the most appropriate management of the patient, with regard to both the calcium‐related phenotype and any associated clinical features, and also to allow the identification of other family members who may be at risk of disease. Genetic testing forms an important tool in the investigation of PHPT and HP patients and is usually reserved for those deemed to be an increased risk of a monogenic disorder. However, identifying those suitable for testing requires a thorough clinical evaluation of the patient, as well as an understanding of the diversity of relevant phenotypes and their genetic basis. This review aims to provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders, primarily focusing on those associated with abnormal calcium homeostasis, and aims to provide a practical guide to the implementation of genetic testing in the clinic.

Finding the broken helix: The mainstreaming of genomic medicine into clinical biochemistry

“…12 • Calcium-related disorders caused by variants in the calcium-sensing receptor. 13 • Variants that cause hypophosphataemia that mostly go undiagnosed in many individuals. 14 • Endocrine-related conditions such as MODY, MEN and phaeochromocytoma.…”

Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity

“…Unlike the predominant class of de novo mutations ( 51 , 52 ), this subtle interchange of isosteric aromatic rings is shared by the proband’s father and hence is compatible with either female or male somatic phenotypes. Exemplifying incomplete penetrance as often encountered among monogenic endocrine syndromes ( 53 – 55 ), inherited Swyer mutations provide an experimental opportunity to define molecular mechanisms at the borderline of genetic function ( 36 , 56 , 57 ). The divergent developmental outcomes—fertile father and sterile XY daughter ( 17 )—stand in striking contrast to the chemical similarity between Tyr and Phe.…”

Editorial for Clinical Endocrinology special issue on “Genetics in Endocrinology”

“…8 Paul Newey, Fadil Hannan, Abbie Wilson and Rajesh Thakker provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders and provide expert advice on the implementation of clinical genetic testing for these conditions. 9 Finally, Carla Moran and colleagues outline the genetic disorders of thyroid development, hormone biosynthesis and signalling and provide a clear description of associated phenotypes and an update on confirmed pathogenic variants in key genes. 10 We are grateful to all who contributed to this special edition and hope that these articles provide a useful update and help promote further clinical and academic advances in the diagnosis and management of rare and hereditary endocrine conditions.…”

“…Tansit Saengkaew and Sasha Howard describe recent advances in the understanding of biological mechanisms underpinning delayed puberty 8 . Paul Newey, Fadil Hannan, Abbie Wilson and Rajesh Thakker provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders and provide expert advice on the implementation of clinical genetic testing for these conditions 9 10 …”