Exome Sequencing in Patients with Primary Hyperparathyroidism Identifies Pathogenic Variants after Negative Panel Testing
Clinical Genetics and Therapeutics
-
Primary Categories:
- Clinical-Adult
-
Secondary Categories:
- Clinical-Adult & Pediatric
Introduction:
Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by increased levels of serum parathyroid hormone and hypercalcemia. Although frequently sporadic, some cases are familial (isolated or syndromic) and caused by pathogenic variants in at least eight genes: AP2S1, CASR, CDC73, CDKN1B, GNA11, MEN1, RET, and TRPV6. The diagnostic rate of genetic testing for hereditary PHPT depends on testing criteria and genes included in testing but typically ranges from 10-30%, with higher diagnostic rates in populations with a family history of a PHPT-related condition. Genetic testing provides valuable information for establishing a diagnosis and can help guide patient management, including surgical decision-making and screening recommendations, as well as identify other family members who may also be affected. Although no consensus exists, some groups recommend genetic testing for patients with PHPT who are under the age of 30, have multiglandular involvement, or have a family history of hypercalcemia or a PHPT-related condition.
Methods:
We reviewed medical records of all unrelated patients referred for a genetic evaluation for PHPT to the Banner Health Medical Genetics clinic from October 2022 to July 2024. Patients who underwent genetic testing via multi-gene panel including the eight genes listed above or exome sequencing (ES) were included in the study. The diagnostic rate was calculated for all patients and stratified by genetic testing methodology. Data was also collected to provide further insight into the genetic and phenotypic features of the patients.
Results:
A total of 26 patients were referred for PHPT and underwent genetic testing. All patients had testing with a multi-gene panel, and seven patients (26.9%) had additional ES due to unusual phenotypic features. For the multi-gene panel testing, 4 individuals (15.4%) received a positive result, 20 individuals (76.9%) received a negative result, and 2 individuals (7.7%) received uncertain results. Pathogenic and likely pathogenic variants were identified in CASR (n=1), CDC73 (n=1), GCM2 (n=1) and MEN1 (n=1). Three of the positive results established a diagnosis for patients, leading to a diagnostic yield of 11.5%.
Of the seven patients who underwent ES, two of the individuals (28.6%) received a positive result, one individual (14.3%) received a negative result, and four individuals (57.1%) received uncertain results. Both individuals who received positive results with ES had prior genetic testing via PHPT multi-gene panel that was negative. Pathogenic and likely pathogenic variants identified with ES were ITPR1 (n=1) and KMT2E (n=1). All positive cases led to changes in management.
Conclusion:
This study found a diagnostic rate of genetic testing in patients with PHPT similar to the rate reported in the literature. Importantly, ES was able to identify pathogenic/likely pathogenic variants in genes not included in routine PHPT multi-gene panels. These results highlight the utility of broader testing for patients with endocrine abnormalities, and larger studies will be beneficial to further investigate the utility of ES in these disorders.
Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by increased levels of serum parathyroid hormone and hypercalcemia. Although frequently sporadic, some cases are familial (isolated or syndromic) and caused by pathogenic variants in at least eight genes: AP2S1, CASR, CDC73, CDKN1B, GNA11, MEN1, RET, and TRPV6. The diagnostic rate of genetic testing for hereditary PHPT depends on testing criteria and genes included in testing but typically ranges from 10-30%, with higher diagnostic rates in populations with a family history of a PHPT-related condition. Genetic testing provides valuable information for establishing a diagnosis and can help guide patient management, including surgical decision-making and screening recommendations, as well as identify other family members who may also be affected. Although no consensus exists, some groups recommend genetic testing for patients with PHPT who are under the age of 30, have multiglandular involvement, or have a family history of hypercalcemia or a PHPT-related condition.
Methods:
We reviewed medical records of all unrelated patients referred for a genetic evaluation for PHPT to the Banner Health Medical Genetics clinic from October 2022 to July 2024. Patients who underwent genetic testing via multi-gene panel including the eight genes listed above or exome sequencing (ES) were included in the study. The diagnostic rate was calculated for all patients and stratified by genetic testing methodology. Data was also collected to provide further insight into the genetic and phenotypic features of the patients.
Results:
A total of 26 patients were referred for PHPT and underwent genetic testing. All patients had testing with a multi-gene panel, and seven patients (26.9%) had additional ES due to unusual phenotypic features. For the multi-gene panel testing, 4 individuals (15.4%) received a positive result, 20 individuals (76.9%) received a negative result, and 2 individuals (7.7%) received uncertain results. Pathogenic and likely pathogenic variants were identified in CASR (n=1), CDC73 (n=1), GCM2 (n=1) and MEN1 (n=1). Three of the positive results established a diagnosis for patients, leading to a diagnostic yield of 11.5%.
Of the seven patients who underwent ES, two of the individuals (28.6%) received a positive result, one individual (14.3%) received a negative result, and four individuals (57.1%) received uncertain results. Both individuals who received positive results with ES had prior genetic testing via PHPT multi-gene panel that was negative. Pathogenic and likely pathogenic variants identified with ES were ITPR1 (n=1) and KMT2E (n=1). All positive cases led to changes in management.
Conclusion:
This study found a diagnostic rate of genetic testing in patients with PHPT similar to the rate reported in the literature. Importantly, ES was able to identify pathogenic/likely pathogenic variants in genes not included in routine PHPT multi-gene panels. These results highlight the utility of broader testing for patients with endocrine abnormalities, and larger studies will be beneficial to further investigate the utility of ES in these disorders.