{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:34:16Z","timestamp":1792715656356,"version":"4.5.0"},"reference-count":23,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,6,12]],"date-time":"2020-06-12T00:00:00Z","timestamp":1591920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism\u2010jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost\u2010effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR\u00a0&gt;\u00a00.02 presenting (i) &lt;35\u00a0years of age, or (ii) &lt;45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and\/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR\u00a0&lt;\u00a00.02.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims and Methods<\/jats:title><jats:p>A retrospective review of patients referred for genetic testing over a 4\u00a0year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next\u2010generation sequencing of the following genes; <jats:italic>MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11<\/jats:italic>, and <jats:italic>AP2S1<\/jats:italic> in NHS\u2010accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 121 patients were included in this study (92 female) with a mean age of 41\u00a0years (SD 17). A pathogenic germline variant was identified in 16% (n\u00a0=\u00a019). A pathogenic variant was identified in the PHPTH genes <jats:italic>CDC73<\/jats:italic> in a single patient and <jats:italic>MEN1<\/jats:italic> in six patients (6% of total), in the FHH genes, <jats:italic>CASR<\/jats:italic> in 11 patients and <jats:italic>AP2S1<\/jats:italic> in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re\u2010classification of four of the variants, with two VUS\u2019s in the <jats:italic>CASR<\/jats:italic> gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified <jats:italic>CASR<\/jats:italic> pathogenic variant versus those without (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.0001) was demonstrated in this study. Thirty\u2010three patients were aged over 50\u00a0years and the diagnostic rate of a pathogenic variant was 15.1% in those patients &gt;50\u00a0years of age compared to 15.9% in those &lt;50\u00a0years. Five patients &gt;50\u00a0years and with a CCCR of &lt;0.01, were diagnosed with a pathogenic variant in <jats:italic>CASR<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re\u2010evaluating VUS\u2019s in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.14254","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T06:53:19Z","timestamp":1589957599000},"page":"409-418","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort"],"prefix":"10.1111","volume":"93","author":[{"given":"Sashi","family":"Mariathasan","sequence":"first","affiliation":[{"name":"Department of Endocrinology Cambridge University Hospital NHS Foundation Trust  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina A.","family":"Andrews","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Cambridge 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