SAT-746 Gain-of-Function CASR variants Identified as a Major Genetic Contributor of Non-Surgical Hypoparathyroidism: Findings from Over 300 Participants in a Sponsored Genetic Testing Program
Notice bibliographique
Résumé
Abstract Disclosure: M. Mannstadt: Advisor and research grants Calcilytix, Takeda, Amolyt. A. Mathew: BridgeBio Employee. A. Sridhar: BridgeBio Employee. L.S. Smith: BridgeBio Employee. M. Roberts: BridgeBio Employee. S. Adler: BridgeBio Employee. 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. Presentation: Saturday, July 12, 2025
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».