MON-761 - Genetic Testing of over 400 Individuals with Non-Surgical Hypoparathyroidism Shows Gain-of-Function CASR Variants as the Most Common Genetic Cause Identified

Hypoparathyroidism is a rare endocrine disorder characterized by low serum calcium with undetectable or inappropriately low parathyroid hormone levels, leading to disrupted mineral homeostasis. Hypoparathyroidism is most often caused by inadvertent injury to or removal of the parathyroid glands during neck surgery. Increasingly, genetic causes are being recognized as diagnostic testing expands and awareness for non-surgical etiologies grows. Genetic forms of hypoparathyroidism may present as isolated disease or as part of a broader syndrome, and include disorders affecting parathyroid gland development, parathyroid hormone synthesis or secretion, and autoimmune-mediated injury to the parathyroid glands.

Individuals with a clinical diagnosis of non-surgical hypoparathyroidism, a positive family history, or suspicion of a genetic etiology are eligible to enroll 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 446 participants (mean age 29 years, range 0 – 83 years) were tested during 2020 – 2025. 294 pathogenic or likely pathogenic variants or variants of uncertain significance were identified across 222 individuals (50%). Among these 222 individuals, CASR was the most frequently affected (40%), followed by AIRE (18%), GATA3 (10%), TBX1 (10%), GNA11 (6%), DHCR7 (4%), GCM2 (4%), SLC12A3 (4%), CHD7 (3%), ACADM (3%), HADHA (3%), FAM111A (2%), SEMA3E (2%), HADHB (2%), CNNM2 (1%), EGF (1%), NEBL (1%), CLDN19 (1%), PTH (1%), TRPM6 (1%), and CLDN16, FXYD2, KCNA1, SOX3, and TBCE (each under 1%). Notably, 60 individuals had more than one variant identified, reflecting either multiple variants within a single gene or variants identified in multiple genes.

In non-surgical hypoparathyroidism without another clear cause, genetic testing and family evaluation are recommended by the current practice guidelines. Identification of genetic etiology can clarify the underlying defect, guide therapy selection, and prompt targeted evaluation and counseling, consistent with recent adult clinical-practice guidance and best practice recommendations. In this cohort, the most common genetic form of hypoparathyroidism was autosomal dominant hypocalcemia type 1, caused by gain-of-function CASR variants (20% of the total population; 88/446). Overall, genetic testing offers a practical, high-yield pathway to establish definitive diagnoses in non-surgical hypoparathyroidism and, consistent with consensus guidance, may thus enable informed counseling for patients and families, better targeted evaluation, and more precise management.

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