SAT231 Next-generation Sequencing For Detection Of Underlying Genetic Causes Of Nonsurgical Hypoparathyroidism: Preliminary Results From A Sponsored Testing Program
Authors: Mannstadt Michael , Mathew Arun , Sridhar Ananth , Stapleton Smith Lyndsay , Scott Roberts Mary , Adler Scott 
Published: October 2023

Disclosure: M. Mannstadt: Advisory Board Member; Self; Takeda, Calcilytix, Amolyt. Research Investigator; Self; Takeda, Calcilytix, Amolyt. A. Mathew: Employee; Self; BridgeBio Pharma. A. Sridhar: Employee; Self; BridgeBio Pharma. L.S. Smith: Employee; Self; BridgeBio Pharma. M. Roberts: Employee; Self; BridgeBio Pharma. S. Adler: Employee; Self; BridgeBio Pharma.

Hypoparathyroidism is a rare endocrine disorder characterized by inadequate production of parathyroid hormone to maintain normal blood calcium levels. Hypoparathyroidism is most frequently caused by damage to or removal of the parathyroid glands but can also be associated with genetic etiologies. Genetic forms of hypoparathyroidism can present as isolated or as part of a syndrome and include disorders of parathyroid gland formation, parathyroid hormone secretion, and damage to the parathyroid gland through autoimmunity. Genetic testing may uncover the underlying etiology of nonsurgical hypoparathyroidism and can help confirm clinical diagnosis, guide medical treatment, and identify affected family members. A sponsored genetic testing program was made available for patients with suspected genetic hypoparathyroidism who met program eligibility criteria. The next-generation sequencing panel has evolved to include 26 genes known to be 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 169 samples between December 2020 and December 2022 were tested from participants with a mean±SD age of 23.4±20.4 (range 0-81) who were diagnosed with nonsurgical/idiopathic hypoparathyroidism (73.9%), hypocalcemia suspected to be of genetic cause (23.7%) or had a relative with a confirmed diagnosis of genetic hypoparathyroidism (2.4%). Pathogenic or likely pathogenic variants, and variants of uncertain significance were identified in 64 individuals (37.9%). Amongst these 64 participants, 77 variants were detected with 46.9% of variant harboring individuals documented as having unknown or no family history. In order of frequency, the relative number of individuals with detected variants are as follows: CASR 56.3% (36/64), AIRE 12.5% (8/64), TBX1 9.38% (6/64), GATA3 7.8% (5/64), GNA11 6.25% (4/64), CHD7 3.13% (2/64), FAM111A 3.13% (2/64), PTH 3.13% (2/64), ACADM 1.6% (1/64), GCM2 1.6% (1/64), HADHB 1.6% (1/64) and TBCE 1.6% (1/64). Of note, 5 individuals had variants identified in more than 1 gene. Notably, these data demonstrate that genetic testing may identify clinically-relevant variants in approximately 2 of 5 individuals with nonsurgical hypoparathyroidism. The most common genetic form of hypoparathyroidism was found to be autosomal dominant hypocalcemia type 1 (21.3% of individuals tested; 36/169), caused by gain-of-function variants in the CASR gene. Overall, this ongoing sponsored testing program provides an efficient path to aid in the diagnosis of genetic causes and may ultimately improve the understanding and management of nonsurgical hypoparathyroidism.

Presentation: Saturday, June 17, 2023