Endocrine Abstracts

JOINT1543

Hypoparathyroidism is a rare condition characterized by insufficient production of parathyroid hormone, resulting in low serum calcium and an imbalance in mineral homeostasis. Hypoparathyroidism is most commonly caused by damage to or removal of parathyroid glands during surgery, however, genetic causes have become increasingly recognized with advances in genetic testing and growing awareness of non-surgical etiologies. Genetic forms of hypoparathyroidism can occur in isolation or as part of a syndrome, and include disorders related to the formation of parathyroid glands, secretion of parathyroid hormone, and autoimmune damage to the parathyroid glands. Individuals with a clinical diagnosis of non-surgical hypoparathyroidism, positive family history or suspicion of genetic hypoparathyroidism, are eligible to participate in a no-charge sponsored genetic testing program in the United States and Canada. The next-generation sequencing panel leveraging a whole exome backbone includes 26 genes associated with hypoparathyroidism: ACADM, AIRE, ATP1A1, CASR, CHD7, CLDN16, CLDN19, CNNM2, DHCR7, EGF, FAM111A, FXYD2, GATA3, GCM2, GNA11, HADHA, HADHB, KCNA1, NEBL, PTH, SEMA3E, SLC12A3, SOX3, TBCE, TBX1 and TRPM6. A total of 327 samples were tested over four years (2020 – 2024) from participants with a mean age of 26. 7 years (range 0-81). 191 variants were identified in 149 individuals (46%) which were classified as pathogenic, likely pathogenic, or variants of uncertain significance. Among these 149 individuals with detected variants, CASR was the most frequently affected (35%), followed by AIRE (17%), GATA3 (10%), TBX1 (7%), HADHA (3%), GNA11 (3%), GCM2 (3%), SEMA3E (2%), SLC12A3 (2%), NEBL (2%), DHCR7 (2%), HADHB (2%), FAM111A (2%), CHD7 (2%), ACADM (1%), TRPM6 (1%), EGF (1%), PTH (1%), KCNA1 (1%), CNNM2 (1%), CLDN19 (1%), and TBCE (1%). Notably, 36 individuals had variants identified in multiple genes. Genetic etiologies should be considered in all patients with hypoparathyroidism without a history of neck surgery as the identification of a genetic etiology can impact patient management and guide further medical evaluation. In our data, the most common genetic form of hypoparathyroidism was found to be autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function variants in the CASR gene (18. 4%; 60/327). An ongoing global Phase 3 study [NCT05680818] is investigating encaleret, an oral calcilytic, which has the potential to be the first targeted treatment for ADH1. The sponsored genetic testing program offers an efficient pathway for diagnosing genetic causes in patients with non-surgical hypoparathyroidism and, in accordance with consensus guidelines, enables improved care for those with an identified genetic etiology.