Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of a telomere biology disorder
Establishing a diagnosis of a telomere biology disorder, allowing for appropriate management and surveillance for disease features based on the gene and/or variant involved
Identifying disease-causing variants within genes known to be associated with increased risk for telomere defects, allowing for predictive testing of at-risk family members
This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 18 genes associated with telomere biology disorders: ACD, CTC1, DKC1, LIG4, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, USB1, WRAP53, and ZCCHC8. See Targeted Genes and Methodology Details for Telomere Biology Disorders Gene Panel and Method Description for additional details
Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for telomere biology disorders.
| Test Id | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULFB | Fibroblast Culture for Genetic Test | Yes | No |
For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Sequence Capture and Targeted Next-Generation Sequencing (NGS) followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing
NextGen Sequencing Test
Aplastic anemia
Bone marrow failure syndrome
Cerebroretinal microangiopathy with calcifications and cysts
Coats plus syndrome
Clericuzio syndrome
Cutaneous malignant melanoma
Dyskeratosis congenita
Hoyeraal Hreidarsson syndrome (HHS)
Idiopathic Pulmonary Fibrosis
Poikiloderma with neutropenia
Revesz syndrome
Short telomere syndrome
Telemeropathy
DNA ligase IV deficiency
For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Varies
Targeted testing for familial variants (also called site-specific or known variants testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about testing option, call 800-533-1710.
Specimen preferred to arrive within 96 hours of collection.
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Any anticoagulant
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated
Specimen Type: Skin biopsy
Supplies: Fibroblast Biopsy Transport Media (T115)
Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.
Specimen Volume: 4-mm punch
Specimen Stability Information: Refrigerated (preferred)/Ambient
Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing, Chorionic Villi/Products of Conception/Tissue. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Cultured fibroblasts
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy from another laboratory. Cultured cells from a prenatal specimen will not be accepted.
Specimen Stability Information: Ambient (preferred)/Refrigerated (<24 hours)
Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing, Chorionic Villi/Products of Conception/Tissue. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing (Spanish) (T826)
2. Molecular Genetics: Congenital Inherited Diseases Patient Information (T521)
Blood: 1 mL; Skin biopsy or cultured fibroblasts: See Specimen Required
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Varies | Varies | ||
Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of a telomere biology disorder
Establishing a diagnosis of a telomere biology disorder, allowing for appropriate management and surveillance for disease features based on the gene and/or variant involved
Identifying disease-causing variants within genes known to be associated with increased risk for telomere defects, allowing for predictive testing of at-risk family members
This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 18 genes associated with telomere biology disorders: ACD, CTC1, DKC1, LIG4, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, USB1, WRAP53, and ZCCHC8. See Targeted Genes and Methodology Details for Telomere Biology Disorders Gene Panel and Method Description for additional details
Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for telomere biology disorders.
For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Telomeres are highly specialized structures composed of TTAGGG nucleotide repeats and proteins that protect chromosome ends. Under normal circumstances, telomeres shorten with every cycle of DNA replication. Telomerase is an enzyme complex that can extend the length of the telomere, thus helping to slow the shortening process. Telomerase is most active in highly proliferative tissues, such as lymphocytes, skin, intestine, and bone marrow.
Telomere biology disorders (TBD) include a complex group of syndromes characterized by abnormally short telomeres. Telomere length analysis in leukocyte subsets is usually performed by flow fluorescent in situ hybridization. The severity of TBD syndromes is variable, and they may present in children or adults. Symptoms of TBD include bone marrow failure, pulmonary fibrosis, liver disease, gastrointestinal disease, and mucocutaneous abnormalities. The prevalence of cancer in the short telomere syndromes is increased. These cancers are mainly hematological malignancies, such as myelodysplastic syndrome and acute myelogenous leukemia, although some solid tumor prevalence is also increased (eg, oral squamous cell carcinoma). Recognition and diagnosis of underlying TBD is important, as it can help guide treatment decisions.
Dyskeratosis congenita (DC) was the first TBD to be described. The subsets of DC include classic DC, Hoyeraal Hreidarsson syndrome (HHS), Revesz syndrome, DC-like conditions, Coats plus syndrome, and isolated subtypes.
Patients with the classic forms of DC are usually diagnosed in childhood with a triad of mucocutaneous features, including dysplastic nails, anomalies of skin pigmentation, and oral leukoplakia. Other features may include bone marrow failure, gastrointestinal disease, liver disease, pulmonary fibrosis, a predisposition to certain cancers, and other medical problems. Alternatively, some patients may have one of the 3 classic features of classic DC along with a hypocellular bone marrow. These patients all have very short telomeres (<1% percentile of age) in leukocytes.
Patients with HHS have the features of classic DC but additionally have cerebellar hypoplasia, neurological conditions, and severe immunodeficiency. They can also have low T-cell numbers with severe B and natural killer (NK) cell lymphopenia (T+/-B- NK-) reminiscent of severe combined immunodeficiency.
In Revesz syndrome, patients have bilateral exudative retinopathy along with other features of DC. Coats plus syndrome is also characterized by bilateral exudative retinopathy in addition to gastrointestinal problems and other symptoms.
When a TBD manifests in adulthood, the presentation can be variable according to the severity of the telomere length defect relative to age. A broad umbrella of clinical features could include bone marrow failure, pulmonary fibrosis, liver disease not otherwise classified, myelodysplastic syndrome, acute myeloid leukemia, or early onset of malignancies within the DC grouping.
A classification of DC-like may be applied for patients who do not meet the diagnostic criteria of DC but have several features reminiscent of the disease.. This could include presence of bone marrow failure, developmental delay, familial history of pulmonary fibrosis, and no other clear diagnosis.
TBD can be inherited in a variety of patterns, including X-linked recessive, autosomal dominant, and autosomal recessive. Approximately 60% to 80% of patients with TBD have variants in the genes evaluated by this panel. In autosomal dominant DC, phenotypes may present at a younger age and more severely in successive generations (genetic anticipation). The genetic anticipation is mediated by the shortened telomeres that are inherited together with the disease-causing variant.
It is increasingly recognized that TBD also include syndromes characterized by abnormally long telomeres. Telomere length is controlled, and like short telomeres, long telomeres also have consequences, mainly increased risk of cancers. The genetic basis of these short and long telomere syndromes may be linked to different disease-causing variants in the same genes. Loss-of-function variants in TERT lead to short telomere syndromes as described earlier, whereas gain-of-function variants lead to increased telomere length and autosomal dominant familial melanoma. Similarly, disease-causing variants in ACD and TINF2 have been described to cause both long and short telomers. Long telomeres caused by these variants lead to increased cancer risk (familial melanoma and thyroid cancer).
An interpretive report will be provided
All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Clinical Correlations:
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.
If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.
To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact Mayo Clinic Laboratories genetic counselors at 800-533-1710.
Technical Limitations:
Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.
There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.
This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.
Deletion/Duplication Analysis:
This analysis targets single and multi-exon deletions/duplications; however, in some instances, single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.
This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.
Genes may be added or removed based on updated clinical relevance. Refer to the Targeted Genes and Methodology Details for Telomere Biology Disorders Gene Panel for the most up to date list of genes included in this test. For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.
If the patient has had an allogeneic hematopoietic stem cell transplant or a recent non-leukoreduced blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.
Reclassification of Variants:
Currently, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages health care providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time. Due to broadening genetic knowledge, it is possible that the laboratory may discover new information of relevance to the patient. Should that occur, the laboratory may issue an amended report.
Variant Evaluation:
Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline.(1) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.
Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.
Rarely, incidental or secondary findings may implicate another predisposition or presence of active disease. These findings will be carefully reviewed to determine whether they will be reported.
1. Richards S, Aziz N, Bale S, et al; ACMG Laboratory Quality Assurance Committee: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424
2. Podlevsky JD, Bley CJ, Omana RV, Qi X, Chen JJL: The telomerase database. Nucleic Acids Res. 2008 Jan;36(Database issue):D339-343. doi: 10.1093/nar/gkm700
3. Armanios M: The role of telomeres in human disease. Annu Rev Genomics Hum Genet. 2022 Aug 31;23:363-381. doi: 10.1146/annurev-genom-010422-091101
4. Bluteau O, Sebert M, Leblanc T, et al: A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood. 2018 Feb 15;131(7):717-732. doi: 10.1182/blood-2017-09-806489
5. Lai TP, Wright WE, Shay JW: Comparison of telomere length measurement methods. Philos Trans R Soc Lond B Biol Sci. 2018 Mar 5;373(1741):20160451. doi: 10.1098/rstb.2016.0451
6. Niewisch MR, Savage SA: An update on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. 2019 Dec;12(12):1037-1052. doi: 10.1080/17474086.2019.1662720
7. Grill S, Nandakumar J: Molecular mechanisms of telomere biology disorders. J Biol Chem. 2021 Jan-Jun;296:100064. doi: 10.1074/jbc.REV120.014017
Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions/insertions (delins) less than 40 base pairs (bp), and above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.
There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. See Targeted Genes and Methodology Details for Telomere Biology Disorders Gene Panel for details regarding the targeted genes analyzed for each test and specific gene regions not routinely covered.(Unpublished Mayo method)
Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.
Genes analyzed: ACD, CTC1, DKC1, LIG4, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, USB1, WRAP53, ZCCHC8
Varies
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.
81443
88233- Tissue culture, skin, solid tissue biopsy (if appropriate)
88240- Cryopreservation (if appropriate)
| Test Id | Test Order Name | Order LOINC Value |
|---|---|---|
| TELDP | Telomere Disorders Gene Panel | 35463-9 |
| Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
|---|---|---|
| 619887 | Test Description | 62364-5 |
| 619888 | Specimen | 31208-2 |
| 619889 | Source | 31208-2 |
| 619890 | Result Summary | 50397-9 |
| 619891 | Result | 82939-0 |
| 619892 | Interpretation | 69047-9 |
| 619893 | Additional Results | 82939-0 |
| 619894 | Resources | 99622-3 |
| 619895 | Additional Information | 48767-8 |
| 619896 | Method | 85069-3 |
| 619897 | Genes Analyzed | 82939-0 |
| 619898 | Disclaimer | 62364-5 |
| 619899 | Released By | 18771-6 |