Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

Abstract

Recent advances in DNA sequencing technology have led to an unprecedented period of disease‐gene discovery offering many new opportunities for genetic testing in the clinical setting. Endocrinology has seen a rapid expansion in the taxonomy of monogenic disorders, which can be detected by an expanding portfolio of genetic tests in both diagnostic and predictive settings. Successful testing relies on many factors including the ability to identify those at increased risk of genetic disease in the busy clinic as well as a working knowledge of the various testing platforms and their limitations. The clinical utility of a given test is dependent upon many factors, which include the reliability of the genetic testing platform, the accuracy of the test result interpretation and knowledge of disease penetrance and expression. The increasing adoption of “high‐content” genetic testing based on next‐generation sequencing (NGS) to diagnose hereditary endocrine disorders brings a number of challenges including the potential for uncertain test results and/or genetic findings unrelated to the indication for testing. Therefore, it is increasingly important that the clinician is aware of the current evolution in genetic testing, and understands the different settings in which it may be employed. This review provides an overview of the genetic testing workflow, focusing on each of the major components required for successful testing in adult and paediatric endocrine settings. In addition, the challenges of variant interpretation are highlighted, as are issues related to informed consent, prenatal diagnosis and predictive testing. Finally, the future directions of genetic testing relevant to endocrinology are discussed.

Genetics of monogenic disorders of calcium and bone metabolism

“…Monogenic disorders affecting calcium and bone metabolism frequently arise from germline mutations affecting the coding region of the responsible gene and are predominantly inherited as autosomal or X-linked traits (Tables 1-3). 1,2 This includes autosomal dominant (e.g., multiple endocrine neoplasia type 1 [MEN1] and type 2A…”

“…Undertaking genetic testing in individuals with a potential monogenic disorder has several potential benefits. 1,31 Confirmation of a genetic diagnosis may not only facilitate appropriate treatment (e.g., conservative management of FHH, surgical approach for MEN1-related PHPT) but also allow the identification of associated features that are not clinically apparent (e.g., nonfunctioning pancreatic neuroendocrine tumours in MEN1). In some instance, a genetic diagnosis may facilitate personalized treatment strategies (e.g., use of enzymereplacement therapy with asfotase-alfa to treat paediatric-onset hypophosphatasia, or use of the anti-fibroblast growth factor (FGF)23 monoclonal antibody burosumab to treat children with X-linked hypophosphataemic rickets).…”

“…[32][33][34] Furthermore, establishing a genetic diagnosis may facilitate: predictive testing in asymptomatic family members; preconception genetic counselling; prenatal genetic testing; and in some settings preimplantation genetic diagnosis. 1 Genetic testing may also resolve diagnostic uncertainty arising from phenocopies in which a patient manifesting the clinical phenotype of a particular genetic disorder is found not to harbour the expected gene mutation. Indeed, phenocopies involving patients with clinical manifestations of MEN1, MEN2A, HPT-JT, and FHH are widely reported.…”

A practical guide to genetic testing in endocrinology

“…Available genetic tests include low resolution genome‐wide assays, targeted approaches such as single gene or gene panel tests, or a high‐resolution agnostic approach using whole genome sequencing (WGS) to interrogate every single base pair in the entire genome. The advantages and disadvantages of each test are described more fully in these reviews 16–18 …”

“…The advantages and disadvantages of each test are described more fully in these reviews. [16][17][18] Cytogenetic testing interrogates the entire genome at low resolution…”