Endocrine Abstracts

Introduction: The successful implementation of clinical genetic testing relies on accurate variant interpretation, as misclassification can result in significant harm to the patient and wider family. Missense single nucleotide variants (SNVs) pose a particular challenge, with current interpretation methods often unable to differentiate pathogenic variants from rare neutral variants, resulting in high numbers of variants of uncertain significance (VUS), and diagnostic uncertain...

Background: Advances in next-generation sequencing facilitate the simultaneous evaluation of large numbers of cancer predisposition genes (CPGs) in patients with cancer irrespective of family history or tumour phenotype. Several studies have reported the frequent occurrence of germline mutations in CPGs in patients with discordant cancer types raising the possibility of novel gene-cancer associations. The current study aimed to evaluate the significance of germline mutations i...

Background: Establishing a genetic diagnosis in patients presenting with potential monogenic endocrine disorders can provide benefits for the individual and wider family. Next-generation sequencing (NGS) gene panels provide a time- and cost-efficient platform for testing. A Scottish NGS endocrine testing platform, comprising 30 genes (11 individual panels), was established in 2018. A national genomic test-directory provides eligibility criteria for testing, bu...

Background: Identifying individuals harbouring germline mutations in hereditary cancer genes provides opportunities for tumour surveillance programs, disease-specific treatment and cascade testing in family members but is reliant on accurate variant interpretation, which may be confounded by imprecise methods for ascribing pathogenicity. Where insufficient evidence supports a definitive classification, ‘variant of uncertain significance’ (VUS) status is applied, whic...

Background: Autosomal dominant hypocalcaemia (ADH) is most commonly due to activating mutations in the Calcium Sensing Receptor (ADH Type 1), in which treatment with vitamin D analogues is frequently associated with hypercalciuria. More recently, activating mutations in the alpha-subunit of the G-protein α-11 (Gα11), encoded by GNA11, have been identified in a small number of ADH kindreds (ADH Type 2). The impact of vitamin D analogue treatment in ADH2 patie...