The CDC73 gene is associated with autosomal dominant hyperparathyroidism-jaw tumor syndrome (HPT-JT), parathyroid carcinoma, and familial isolated hyperparathyroidism (FIH) (MedGen UID: 310065, 146361, 333554), collectively referred to as CDC73-related conditions.
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The CDC73 gene encodes parafibromin, which is thought to be involved in the regulation of gene transcription, along with cell growth and proliferation. The CDC73 gene also appears to be involved with the organization of the cytoskeleton in cells.
MedGen UID: 146361
CDC73-related conditions include familial isolated hyperparathyroidism (FIHP), parathyroid carcinoma, and hyperparathyroidism-jaw tumor (HPT-JT) syndrome (PMID: 23293331, 23029104, 12434154). FIHP and hereditary parathyroid carcinoma lack additional extra-organ involvement, but HPT-JT is typically a multi-systemic neoplastic condition. Features include:
Not everyone with a CDC73 pathogenic variant will manifest symptoms, but up to 90% will develop a CDC73-related condition. In HPT-JT, the onset of primary hyperparathyroidism (PHPT) typically occurs in adolescence or early adulthood; 80% of cases will develop PHPT by age 40 (PMID: 20301744).
It has been suggested that CDC73-related disorders be considered as part of a single spectrum. Supportive evidence includes the highly variable expression of symptoms observed in individuals with CDC73 pathogenic variants and that all three conditions are caused by the same gene (PMID: 24678936, 25959515, 24402736, 25511968).
There is preliminary evidence to suggest HPT-JT may be associated with benign and malignant uterine tumors, however, the available data are insufficient to make a clear determination regarding this association. Therefore, CDC73 is considered a “preliminary evidence gene” in its association with uterine cancer by Invitae (PMID: 15606373, 20301744). preliminary evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary evidence genes.
CDC73 is a tumor-suppressor gene, meaning its function is to help control rate of growth and cell division in the body. This gene is likely involved in transcriptional and post-transcriptional control pathways and may be involved in cell-cycle progression ( UniProt consortium, UniProtKB – Q6P1J9 (CDC73_HUMAN); http://www.uniprot.org/uniprot/Q6P1J9. Accessed September 2015). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers is increased.
Hereditary predisposition to cancer due to pathogenic variants in the CDC73 gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it).
There are no established screening or surveillance guidelines for individuals with a pathogenic CDC73 variant, but the following have been suggested to establish the extent of disease in an individual diagnosed with a CDC73-related disorder (PMID: 20301744):
The following surveillance guidelines have been proposed (PMID: 20301744):
In addition, it is recommended that individuals with CDC73-related conditions avoid dehydration, radiation exposure, and biopsy of extra-thyroid neck tissue, which may increase the risk of seeding a possible parathyroid carcinoma (PMID: 20301744):
An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.
Even though the data regarding CDC73 are limited, knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding CDC73 are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to consider implementing proposed screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.
Review date: September 2015
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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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