Paul J. Newey

Utility of Population-Level DNA Sequence Data in the Diagnosis of Hereditary Endocrine Disease

Context: Genetic testing is increasingly used for clinical diagnosis, although variant interpretation presents a major challenge because of high background rates of rare coding-region variation, which may contribute to inaccurate estimates of variant pathogenicity and disease penetrance. Objective: To use the Exome Aggregation Consortium (ExAC) data set to determine the background population frequencies of rare germline coding-region variants in genes associated with hereditary endocrine disease and to evaluate the clinical utility of these data. Design, Setting, Participants: Cumulative frequencies of rare nonsynonymous single-nucleotide variants were established for 38 endocrine disease genes in 60,706 unrelated control individuals. The utility of gene-level and variant-level metrics of tolerability was assessed, and the pathogenicity and penetrance of germline variants previously associated with endocrine disease evaluated. Results: The frequency of rare coding-region variants differed markedly between genes and was correlated with the degree of evolutionary conservation. Genes associated with dominant monogenic endocrine disorders typically harbored fewer rare missense and/or loss-of-function variants than expected. In silico variant prediction tools demonstrated low clinical specificity. The frequency of several endocrine disease‒associated variants in the ExAC cohort far exceeded estimates of disease prevalence, indicating either misclassification or overestimation of disease penetrance. Finally, we illustrate how rare variant frequencies may be used to anticipate expected rates of background rare variation when performing disease-targeted genetic testing. Conclusions: Quantifying the frequency and spectrum of rare variation using population-level sequence data facilitates improved estimates of variant pathogenicity and penetrance and should be incorporated into the clinical decision-making algorithm when undertaking genetic testing.

Pathogenicity and penetrance of germline SDHA variants in pheochromocytoma and paraganglioma (PPGL)

Abstract Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of “at-risk” first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.

The epidemiology of hyperprolactinaemia over 20 years in the Tayside region of Scotland: The Prolactin Epidemiology, Audit, and Research Study (PROLEARS)

To estimate the prevalence and incidence of hyperprolactinaemia. Hyperprolactinaemia is a common problem in endocrine practice, but its epidemiology has not been accurately established.

Genetic Approaches to Metabolic Bone Diseases: Genetic Approaches to Metabolic Bone Diseases

Metabolic bone diseases comprise a diverse group of disorders characterized by alterations in skeletal homeostasis, and are often associated with abnormal circulating concentrations of calcium, phosphate or vitamin D metabolites. These diseases commonly have a genetic basis and represent either a monogenic disorder due to a germline or somatic single gene mutation, or an oligogenic or polygenic disorder that involves variants in more than one gene. Germline single gene mutations causing Mendelian diseases typically have a high penetrance, whereas the genetic variations causing oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. Recognition of familial monogenic disorders is of clinical importance to facilitate timely investigations and management of the patient and any affected relatives. The diagnosis of monogenic metabolic bone disease requires careful clinical evaluation of the large diversity of symptoms and signs associated with these disorders. Thus, the clinician must pursue a systematic approach beginning with a detailed history and physical examination, followed by appropriate laboratory and skeletal imaging evaluations. Finally, the clinician must understand the increasing number and complexity of molecular genetic tests available to ensure their appropriate use and interpretation.

Introduction to Genetics of Skeletal and Mineral Metabolic Diseases

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.

Multiple Endocrine Neoplasia Syndromes

Abstract Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN are recognized and referred to as MEN types 1–4, and each form is characterized by the development of tumors within specific endocrine tissues. Each form of MEN is typically inherited as an autosomal dominant syndrome but may occur sporadically; that is, without a family history, although this distinction between sporadic and familial cases may sometimes be challenging. In addition to MEN1-4, six other syndromes which are associated with multiple endocrine and other organ neoplasias (MEONs) are recognized. These include the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, Von Hippel–Lindau disease, Carney complex (CNC), Neurofibromatosis type 1 (NF1), Cowden syndrome (CWD), and McCune–Albright syndrome. Each of these are typically inherited as autosomal dominant disorders, with the exception of McCune–Albright syndrome which is due to a mosaic expression of a postzygotic somatic GNAS mutation. Each MEN and MEONs syndrome is associated with skeletal disease that include osteoporosis, scoliosis, pseudoarthroses, long bone and spinal dysplasias, ossifying tumors, osteochondromyxomas, as well as metastatic involvement.