This test analyzes the CDC73 gene, which is associated with the spectrum of CDC73-related disorders including parathyroid carcinoma, familial isolated hyperparathyroidism (FIHP), and hyperparathyroidism-jaw tumor (HPT-JT) syndrome. HPT-JT is characterized by primary hyperthyroidism that is most often due to a benign pituitary adenoma or pituitary hyperplasia, ossifying jaw fibromas, and renal and uterine lesions.
It is important to confirm a diagnosis of HPT-JT because this condition is associated with increased risk of parathyroid and other cancers. Although many of the typical signs and symptoms of HPT-JT evolve with age, genetic testing by analysis of CDC73 may confirm a diagnosis in early childhood and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
CDC73-related conditions are on clinical spectrum inclusive of familial isolated hyperparathyroidism (FIHP), parathyroid carcinoma, and hyperparathyroidism-jaw tumor (HPT-JT) syndrome. While FIHP and hereditary parathyroid carcinoma lack additional extra-organ involvement, HPT-JT is typically a multi-systemic neoplastic condition. Features include:
While not everyone with a CDC73 pathogenic variant will manifest symptoms, approximately 70% will develop a CDC73-related condition.
In HPT-JT, the onset of primary hyperparathyroidism (PHPT) is typically during adolescence or early adulthood; 80% of cases will develop PHPT by age 40. The risk of parathyroid carcinoma is 10%-15% and there is a 25%-50% risk of developing ossifying jaw fibromas. Approximately 20% of affected individuals develop renal cysts, hamartomas, and more rarely, Wilms tumor; however, the lifetime risk of kidney cancer is currently unclear. Up to 75% of affected females will develop benign or malignant uterine tumors.
The frequency of CDC73 pathogenic variants in individuals with ossifying jaw fibromas is currently unknown; however, an identifiable pathogenic variant is identified in:
Autosomal dominant. Most cases are inherited; the rate of spontaneous de novo mutations is unknown.
The prevalence of CDC73 conditions is currently unknown and appears to be rare.
Analysis of the CDC73 gene may be considered in individuals with the following:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|