Dyskeratosis Congenita
Dyskeratosis Congenita (DC) is an inherited bone marrow failure syndrome primarily caused by defects in the maintenance of chromosome telomeres.
PrintDyskeratosis Congenita (DC) is an inherited bone marrow failure syndrome primarily caused by defects in the maintenance of chromosome telomeres.
Diagnostic criteria for Dyskeratosis Congenita are expanding from the classical triad of nail dystrophy, oral leukoplakia (white keratinized patches), and abnormal, lacy skin pigmentation to encompass the wide range of features related to short telomeres. Short telomeres and mutations in DC-causing genes are also found in a disease spectrum that ranges in severity from the multisystem infantile Hoyeraal-Hreidarsson syndrome, to isolated myelodysplastic syndrome, aplastic anemia, or pulmonary fibrosis, to only mild hematologic abnormalities in middle-age.
Three modes of inheritance and at least seven genes involved in telomere maintenance are associated with Dyskeratosis Congenita. The Ambry SEQUENCE™: Dyskeratosis Congenita is a testing pathway to sequentially analyze six of these genes (DKC1, TINF2, TERT, TERC, NHP, NOP) by full or partial gene sequence analysis. Testing is arranged into three steps for maximum yield and minimum cost and testing time. Analysis of the seventh gene, WRAP53, is available separately. For patients who have had previous genetic testing or whose pedigree strongly suggests a specific mode of inheritance, tests may be ordered individually by gene. Testing through the Ambry SEQUENCE™ identifies mutations in 45-50% of patients.
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome primarily caused by defects in the maintenance of chromosome telomeres. Diagnostic criteria are expanding from the classical triad of nail dystrophy, oral leukoplakia (white keratinized patches), and abnormal skin pigmentation to encompass a wide range of features related to short telomeres. Bone marrow failure, present in 80-90% of patients by age 30, remains the main cause of early mortality.1 Abnormal skin pigmentation and nail changes are usually seen by age 10. Other common clinical manifestations include learning disabilities, pulmonary disease, short stature, dental caries, and prematurely gray hair.1 Short telomeres and mutations in DC-causing genes are also associated with other clinical disorders that vary in severity from the multisystem infantile Hoyeraal-Hreidarsson syndrome to only mild hematologic abnormalities in middle-age.2
DC is a genetically heterogeneous disorder. Three modes of inheritance and at least seven genes are associated with DC. Approximately 30% of all patients have mutations in the X-linked gene DKC1 for dyskerin.3 Autosomal dominant DC results from mutations in exon 6 of the TINF2 gene (approximately 11%)4,5 or in the TERC gene (6%).3 TERT mutations are a rare cause of autosomal dominant or recessive cases (1%).3,6 A small number (<1%) of autosomal recessive cases are attributed to mutations in exon 4 of NHP2 (aka NOLA2)7 and in exon 2 of NOP10 (aka NOLA3).3 Currently, four mutations in WRAP53 have been observed in patients with autosomal recessive DC.8 Testing is available at Ambry Genetics for all seven aforementioned genes, and approximately 45-50% of patients with DC carry disease-causing mutations in these genes.1,4
Due to its marked clinical and genetic heterogeneity, genetic testing is an especially useful diagnostic tool for patients with DC. Knowledge of positive mutation status may have the following benefits for clinical management and counseling:
- enables cancer surveillance in the patient and carrier relatives
- assists in the determination of appropriate therapies for aplastic anemia
- allows exclusion of carrier relatives as potential bone marrow donors
- reveals the increased risk of bone marrow transplant complications including pulmonary and hepatic fibrosis.
The Ambry SEQUENCE: Dyskeratosis Congenita is a testing pathway to sequentially analyze up to six genes causing DC by partial or full gene sequence analysis. Testing is arranged into three steps for maximum yield and minimum cost. Medical personnel may order the complete SEQUENCE, with reflex testing done for steps one through three until causative mutations are detected, or they may choose a single step or pair of steps depending on their patient’s history and presentation.
| SEQUENCE Steps | Indication | Description | Detection Rate | TAT in days |
| Complete | All probands; rare causes included | Step 1, if negative then Step 2, if negative then Step 3 | 45-50% | 14-49 |
| 1 | All probands with no previous testing | Concurrent DKC1 full gene, TINF2 exon 6, and TERC full gene sequence analysis | DCK1: 30% TINF2: 11% TERC: 6% Step 1: ~47% |
14-21 |
| 2 | Step 1 negative probands with possible recessive DC | Concurrent sequence analysis of NHP2 exon 4 and NOP10 exon 2 | Rare, <1% | 7-10 |
| 3 | Step 1 negative probands with possible dominant or recessive DC | TERT full gene sequence analysis | Rare, 1% | 10-21 |
For patients who have had previous genetic testing or whose pedigree strongly suggests a specific mode of inheritance, tests may be ordered individually by gene. Specific mutation analysis for familial mutations in any analyzed gene region is also available.
Each test in the SEQUENCE is a gene sequence analysis performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for the regions specified. DKC1: exons 1-15 plus at least 20 bases into the 5’ and 3’ ends of all the introns. A previously described regulatory mutation at c.-142 is also analyzed. TINF2: exon 6 plus at least 20 bases into the 5’ and 3’ ends of the related introns. TERC: the entire single-exon gene. NHP2: exon 4 plus at least 20 bases into 5’ and 3’ ends of the related introns. NOP10: exon 2 plus at least 20 bases into 5’ and 3’ ends of the related introns. TERT: exons 1-16 plus at least 20 bases into the 5’ and 3’ ends of all the introns.
Additional analysis of the WRAP53 gene sequence may be ordered separately. The Ambry Test: WRAP53 related Dyskeratosis Congenita is a gene sequence analysis performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for the regions specified. WRAP53: exons 1-10 plus at least 20 bases into the 5’ and 3’ ends of all the introns, as well as the 5’UTR region (c.-258 to c. -639).
Testing through the Ambry SEQUENCE: Dyskeratosis Congenita identifies mutations in 45-50% of patients as detailed in the table in the previous section (clinical sensitivity). Approximately 99% of described mutations in the analyzed regions are detectable for six of the seven genes (DKC1, TINF2, TERT, NHP, NOP, WRAP53); for TERC the analytic sensitivity is 90%.
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into OrageneTM DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 μg in TE at 50-100 ng/μl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available for the indication dyskeratosis congenita. Please call an Ambry Genetic Counselor to discuss your case.
| Test Code | Technique | CPT Codes |
|---|---|---|
| 1960 | DKC1 Gene Sequence Analysis | 83891x1, 83894x16, 83898x15, 83904x30, 83909x30, 83912x1 |
| 1980 | TINF2 Gene Sequence Analysis | 83891x1, 83894x2, 83898x1, 83904x2, 83909x2, 83912x1 |
| 2120 | TERC Gene Sequence Analysis | 83891x1, 83894x2, 83898x1, 83904x2, 83909x2, 83912x1 |
| 2140 | Step 3 Only (TERT Gene Sequence Analysis) | 83891x1, 83894x20, 83898x19, 83904x38, 83909x38, 83912x1 |
| 5160 | WRAP53 (TCAB1)- Gene Sequence Analysis | 83891x1, 83894x11, 83898x10, 83904x20, 83909x20, 83912x1 |
| 8160 | DC Steps 1-3 Reflex Option to DKC1, TINF2, TERC, NHP2, NOP10, TERT | 83891x1, 83894x39, 83898x38, 83904x75, 83909x76, 83912x3 |
| 8161 | DC Steps 1-3 Concurrent to DKC1, TINF2, TERC, NHP2, NOP10, TERT | 83891x1, 83894x39, 83898x38, 83904x75, 83909x76, 83912x3 |
| 8162 | Step 1 only (DKC1, TINF2 Exon 6, TERC) | 83891x1, 83894x18, 83898x17, 83904x34, 83909x34, 83912x1 |
| 8163 | Step 1 and Step 2 (DKC1, TINF2, TERC, NHP2, NOP10) | 83891x1, 83894x20, 83898x19, 83904x38, 83909x38, 83912x2 |
| 8164 | Step 2 only (NHP2 exon 4, NOP10 exon 2) | 83891x1, 83894x3, 83898x2, 83904x4, 83909x4, 83912x1 |
| Technique | Days |
|---|---|
| DKC1 Gene Sequence Analysis | 10-21 |
| TINF2 Gene Sequence Analysis | 7-14 |
| TERC Gene Sequence Analysis | 7-14 |
| Step 3 Only (TERT Gene Sequence Analysis) | 10-21 |
| WRAP53 (TCAB1)- Gene Sequence Analysis | 10-21 |
| DC Steps 1-3 Reflex Option to DKC1, TINF2, TERC, NHP2, NOP10, TERT | 10-49 |
| DC Steps 1-3 Concurrent to DKC1, TINF2, TERC, NHP2, NOP10, TERT | 10-28 |
| Step 1 only (DKC1, TINF2 Exon 6, TERC) | 14-21 |
| Step 1 and Step 2 (DKC1, TINF2, TERC, NHP2, NOP10) | 14-35 |
| Step 2 only (NHP2 exon 4, NOP10 exon 2) | 7-14 |
1 Kirwan M, Dokal I. Clin Genet. 2008;73:103-112.
2 Vulliamy TJ, Marrone A, et al. Blood. 2006;107:2680-2685.
3 Walne AJ, Vulliamy T, et al. Hum Mol Genet. 2007:16:1619-1629.
4 Walne AJ, Vulliamy T, et al. Blood. 2008;112:3594-3600.
5 Savage SA, Giri N, et al. Am J Hum Genet. 2008;82:501-509.
6 Marrone A, Walne A, et al. Blood. 2007;110:4198-4205.
7 Vulliamy T, Beswick R, et al. Proc Natl Acad Sci. 2008;105:8073-8078.
8 Zhong F, Savage SA, et al. Genes Dev. 2011;25:11-16.