AUTHOR=García-Castaño Alejandro , Madariaga Leire , Gómez-Conde Sara , González Pedro , Grau Gema , Rica Itxaso , de Nanclares Gustavo Pérez , De la Hoz Ana Belén , Aguayo Aníbal , Martínez Rosa , Urrutia Inés , Gaztambide Sonia ,  Calcium Phosphorus Metabolism Molecular Biology Group , Castaño Luis 

TITLE=Genetic profile of a large Spanish cohort with hypercalcemia

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1297614

DOI=10.3389/fendo.2024.1297614

ISSN=1664-2392

ABSTRACT=<sec><title>Introduction</title><p>The disorders in the metabolism of calcium can present with manifestations that strongly suggest their diagnosis; however, most of the time, the symptoms with which they are expressed are nonspecific or present only as a laboratory finding, usually hypercalcemia. Because many of these disorders have a genetic etiology, in the present study, we sequenced a selection of 55 genes encoding the principal proteins involved in the regulation of calcium metabolism.</p></sec><sec><title>Methods</title><p>A cohort of 79 patients with hypercalcemia were analyzed by next-generation sequencing.</p></sec><sec><title>Results</title><p>The 30% of our cohort presented one pathogenic or likely pathogenic variant in genes associated with hypercalcemia. We confirmed the clinical diagnosis of 17 patients with hypocalciuric hypercalcemia (pathogenic or likely pathogenic variants in the <italic>CASR</italic> and <italic>AP2S1</italic> genes), one patient with neonatal hyperparathyroidism (homozygous pathogenic variant in the <italic>CASR</italic> gene), and another patient with infantile hypercalcemia (two pathogenic variants in compound heterozygous state in the <italic>CYP24A1</italic> gene). However, we also found variants in genes associated with primary hyperparathyroidism (<italic>GCM2</italic>), renal hypophosphatemia with or without rickets (<italic>SLC34A1</italic>, <italic>SLC34A3</italic>, <italic>SLC9A3R1</italic>, <italic>VDR</italic>, and <italic>CYP27B1</italic>), DiGeorge syndrome (<italic>TBX1</italic> and <italic>NEBL</italic>), and hypophosphatasia (<italic>ALPL</italic>). Our genetic study revealed 11 novel variants.</p></sec><sec><title>Conclusions</title><p>Our study demonstrates the importance of genetic analysis through massive sequencing to obtain a clinical diagnosis of certainty. The identification of patients with a genetic cause is important for the appropriate treatment and identification of family members at risk of the disease.</p></sec>