AUTHOR=Mazarico-Altisent Isabel , Capel Ismael , Baena Neus , Bella-Cueto Maria Rosa , Barcons Santi , Guirao Xavier , Pareja Rocío , Muntean Andreea , Arsentales Valeria , Caixàs Assumpta , Rigla Mercedes 

TITLE=Genetic testing for familial hyperparathyroidism: clinical-genetic profile in a Mediterranean cohort

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1244361

DOI=10.3389/fendo.2023.1244361

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>Approximately 10% of primary hyperparathyroidism cases are hereditary, due to germline mutations in certain genes. Although clinically relevant, a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate.</p></sec><sec><title>Methods</title><p>A customized gene panel (<italic>AIP</italic>, <italic>AP2S1</italic>, <italic>CASR</italic>, <italic>CDC73</italic>, <italic>CDKN1A</italic>, <italic>CDKN1B</italic>, <italic>CDKN2B</italic>, <italic>CDKN2C</italic>, <italic>GCM2</italic>, <italic>GNA11</italic>, <italic>MEN1</italic>, <italic>PTH</italic>, <italic>RET</italic>, and <italic>TRPV6</italic>) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age, family history, high-risk histology, associated tumour, multiglandular disease, or recurrent hyperparathyroidism). We aimed to determine the prevalence of germline variants in these patients, to clinically characterize the probands and their relatives, and to compare disease severity in carriers versus those with a negative genetic test.</p></sec><sec><title>Results</title><p>Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of <italic>CDKN1B</italic> (related to MEN4), 1 novel variant of uncertain significance of <italic>CDKN2C</italic>, 4 variants of <italic>CASR</italic> (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of <italic>TRPV6</italic>. Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands.</p></sec><sec><title>Conclusion</title><p>The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features.</p></sec>