This test analyzes seven genes that are associated with dyskeratosis congenita (DC). DC is a clinically and genetically heterogeneous telomere biology disorder characterized by abnormal skin pigmentation, nail dystrophy, oral leukoplakia, and increased risk of progressive bone marrow failure and development of malignancies.
Genetic testing of these genes may confirm a diagnosis 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.
If the patient has undergone a bone marrow transplant prior to genetic testing or currently has a hematological malignancy with actively circulating tumor cells, testing a sample type that is not derived from blood (such as skin biopsy) is warranted. While we do not accept this sample type directly, we can accept DNA derived from skin or muscle, though deletion/duplication analysis is not guaranteed for DNA samples because the success rate varies based on sample quality. Please see our Specimen requirements page for more details.
CTC1 DKC1 NHP2 NOP10 TERC TERT TINF2
CTC1 DKC1 NHP2 NOP10 TERC TERT TINF2
These genes can also be ordered as part of broader panels. Depending on the individual’s clinical and family history, one of these panels may be appropriate and can be ordered at no additional charge.
DC is a telomere biology disorder and is classically characterized by dysplastic nails, lacy reticular pigmentation, and oral leukoplakia. Reduced penetrance is common, so some individuals might not have these symptoms. Individuals with DC have an increased risk of progressive bone marrow failure, myelodysplastic syndrome, acute myelogenous leukemia, solid tumors, and pulmonary fibrosis. These symptoms may be the presenting features in some individuals. Other findings can include abnormal pigmentation changes, eye abnormalities, and dental anomalies. The age of onset is variable and disease presentation can be mild to severe.
Individuals with pathogenic variants in the CTC1 gene may have additional symptoms, including leukoencephalopathy, brain calcifications, and cysts.
A pathogenic variant has been identified in approximately 50% of individuals who meet the clinical diagnostic criteria for DC.
|Gene||Attribution to DC|
The inheritance of DC varies by gene:
The clinical expression of DC is widely variable, even among family members, and the exact penetrance is unclear. However, abnormally short telomeres have been consistently demonstrated in individuals with pathogenic variants in causative genes, regardless of clinical phenotype.
The prevalence is unknown.
Testing for DC should be considered in individuals with a personal history of:
If the patient has undergone a bone marrow transplant prior to genetic testing or currently has a hematological malignancy with actively circulating tumor cells, testing a sample type that is not derived from blood (such as skin biopsy) is warranted. While we do not accept this sample type directly, we can accept gDNA derived from skin or muscle, but deletion/duplication analysis is not guaranteed for gDNA samples because the success rate varies based on sample quality. Please see our Sample requirements page for more details.
Clinical management of DC patients is complex and requires comprehensive coordinated care among specialties. Recommendations for management have been discussed at a DC clinical research workshop held at the NIH in 2008:
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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
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|