DiagnosisClinical Diagnosis Individuals with characteristic clinical findings described below who have very short telomeres and/or a mutation in one of the genes known to be associated with dyskeratosis congenita (DC) should be considered as having DC. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic DC as well as those with very short telomeres and an isolated physical finding [Armanios 2009, Kirwan & Dokal 2009, Savage & Alter 2009, Savage & Bertuch 2010].Dyskeratosis congenita (DC) should be suspected in individuals with the following findings [Vulliamy et al 2006, Savage & Bertuch 2010]:Physical abnormalities At least two features of the classic DC clinical triad (Figure 1):Dysplastic nails. May be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nailsLacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck.Oral leukoplakia One feature of the classic triad plus two or more of the following [Vulliamy et al 2006]: EpiphoraBlepharitisAbnormal eyelashesPrematurely gray hairAlopeciaPeriodontal diseaseTaurodontism (enlarged tooth pulp chambers) or decreased tooth root/crown ratioDevelopmental delayShort statureMicrocephalyHypogonadismEsophageal stenosisUrethral stenosisLiver diseaseOsteoporosisAvascular necrosis of the hips or shoulders.FigureFigure 1. Examples of the dyskeratosis congenita diagnostic triad
A. Skin pigmentation
B. Dysplastic fingernails and toenails
C. Oral leukoplakia Note: Individuals with DC may have none of the above additional findings; the findings may appear or worsen with age.Progressive bone marrow failure (BMF). May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen.Myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). May be the presenting sign.Solid tumors, usually head/neck or anogenital cancer, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC in individuals who do not have BMF. Pulmonary fibrosis. See Primary Pulmonary Fibrosis.TestingTelomere length. Telomeres are long nucleotide repeats (TTAGGG)_n and a protein complex at chromosome ends that are essential to chromosomal integrity. All individuals with a telomere disorder have abnormally short telomeres for their age, as determined by automated multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on white blood cell (WBC) subsets. Telomere length testing for DC and related telomere biology disorders is available from a CLIA-certified laboratory.Telomere length in total leukocytes and in leukocyte subsets (granulocytes, total lymphocytes, naïve T-cells, memory T-cells, B-cells, and natural killer [NK] cells) was determined by flow-FISH on cells from persons with DC, their relatives, and persons with other inherited bone marrow failure syndromes (IBMFS). Data from 400 healthy controls (newborn through age 100 years) was used to generate percentiles of normal telomere length; values below the first percentile for age were considered “very short.” The diagnostic sensitivity and specificity of very short telomeres was more than 90% in total lymphocytes, naïve T-cells, and B-cells for the diagnosis of DC in comparison with healthy relatives of persons with DC or persons with non-DC IBMFS. Rare healthy relatives with very short telomeres were later shown to have mutations in the same DC-related gene as the proband. Evaluation of the panel of six leukocyte subsets provided the greatest degree of sensitivity and specificity; the best statistical performance characteristics were obtained by finding very short telomeres in at least three or four of the subsets; granulocytes were the least specific cell type [Alter et al 2007]. A follow-up study with a much larger sample size confirmed this finding [Alter et al 2012]. It also suggested that if the clinical suspicion of DC is high, total lymphocyte telomere length is sufficient for diagnosis. The positive predictive value was 85% in individuals with telomere length below the first percentile for age and a clinical suspicion of DC. However, in less straightforward cases, the six-panel test may be more sensitive and specific.Note: Another study [Du et al 2009b] performed in a different research laboratory using a different technique suggested that peripheral blood mononuclear cell telomere length was less specific for the diagnosis of classic DC; however, the significant differences between the laboratories and analytic methods used suggest that these studies are not directly comparable. Molecular Genetic Testing Genes. To date, CTC1, DKC1, TERC, TERT, TINF2, WRAP53, NHP2, and NOP10 are the only genes in which mutations are known to cause DC and short telomeres (Figure 2). FigureFigure 2. Telomere length and structure are regulated by a host of proteins. Mutations affecting a subset of these proteins have been implicated in telomere biology disorders. The percentages indicate the approximate number of cases resulting from mutations (more...)Evidence for further locus heterogeneity. Mutations in one of the seven genes mentioned above have been identified in approximately half of individuals who meet clinical diagnostic criteria for DC. Table 1. Summary of Molecular Genetic Testing Used in Dyskeratosis CongenitaView in own windowGene SymbolMode of InheritanceProportion of DC Attributed to Mutations in This Gene ^{1Test MethodMutations DetectedTest AvailabilityDKC1XL 217%-36%Sequence analysis Sequence variants 3, 4ClinicalDeletion / duplication analysis 5, 6 Exonic or whole-gene deletions 7, 8TERCAD 96%-10%Sequence analysisSequence variants 3ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletions 8TERTAD and AR 101%-7%Sequence analysisSequence variants 3ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletions 8TINF2AD 1111%-24%Sequence analysisSequence variants 3, 12ClinicalSequence analysis of select exonsSequence variants of exon 6 13NHP2 AR 14<1%Sequence analysisSequence variants 3ClinicalSequence analysis of select exonsSequence variants of exon 4 13NOP10 AR 15<1%Sequence analysisSequence variants 3, 15ClinicalSequence analysis of select exonsSequence variants of exon 2 15WRAP53 (TCAB1)AR 163%Sequence analysisSequence variants 3ClinicalCTC1AR 171%-3%Sequence analysisSequence variants 3Research only1. Data from Vulliamy et al [2006], Walne et al [2007], Savage et al [2008], Vulliamy et al [2008], Walne et al [2008] 2. Knight et al [1999b]3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. Sequence analysis of genomic DNA cannot detect deletion of an exon(s) or whole-gene deletions on the X chromosome in carrier females.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Deletion/duplication analysis may be useful to confirm a putative exonic or whole-gene DKC1 deletion on the X chromosome in affected males after failure of PCR amplification. If such a deletion is identified in a male, this test would be useful for carrier testing of female relatives.7. One 3’ deletion involving DKC1 in a female carrier of dyskeratosis congenita has been reported [Vulliamy et al 1999].8. No deletions or duplications involving DKC1, TERC, or TERT as causative of dyskeratosis congenita have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)9. Vulliamy et al [2004]10. Marrone et al [2007b], Vulliamy et al [2005] 11. Savage et al [2008]12. Note: All TINF2 mutations described to date have been located in exon 6. 13. All mutations described to date have been located in this exon.14. Vulliamy et al [2008] 15. Walne et al [2007] 16. Zhong et al [2011] 17. Walne et al [2012]Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at www.eurogentest.org [Dokal et al 2011; see full text].Interpretation of test results. Tissue-restricted mosaicism has been observed in a limited number of individuals heterozygous for a TERC germline mutation. Specifically, a pathogenic TERC germline mutation that was not observed by molecular genetic testing of DNA extracted from peripheral blood cells was detected in DNA extracted from other cells (e.g. skin fibroblasts) of the individual [Jongmans et al 2012]. Tissue-restricted mosaicism resulted from revertant somatic mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells, particularly in individuals with DC without bone marrow failure. The assumption is that the selective advantage of the revertant hematopoietic cells allows them to populate the bone marrow, resulting in the inability to detect the mutation in DNA extracted from these cells. To date, this has only been observed in individuals with germline TERC mutations. Molecular genetic testing of a second tissue source should be considered in individuals who meet the diagnostic criteria for DC but do not have a disease-causing mutation identified on molecular genetic testing of peripheral blood cells.For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. Individuals with suspected DC should undergo leukocyte telomere length testing by automated multicolor flow-FISH in the six-cell panel assay. Telomere length less than the first percentile for age in lymphocytes is 97% sensitive and 91% specific for DC. In individuals with complex or atypical DC, the six-cell panel may be more informative than the two-panel test of total lymphocytes and granulocytes [Alter et al 2012].Molecular genetic testing should be considered if telomere length testing reveals telomere lengths less than the first percentile for age. If male, begin with DKC1 sequence analysis. Further molecular genetic testing can be prioritized based on:Likely mode of inheritance as per the family history (Table 1), The probability that mutation of a given gene is causative (Table 1), and The clinical phenotype (see Genotype-Phenotype Correlations).Note: Individuals who appear to fulfill diagnostic criteria for DC (especially those without bone marrow failure) but in whom molecular genetic testing of DNA extracted from peripheral blood fails to identify a disease-causing mutation warrant consideration of testing of a second tissue (e.g., skin fibroblasts) because of the possibility of tissue-restricted mosaicism for a deleterious germline mutation (see Interpretation of test results).Carrier testing for relatives at risk for X-linked dyskeratosis congenita (caused by mutations in DKC1) requires prior identification of the disease-causing mutation in the family.Note: (1) Female carriers are heterozygotes for the X-linked form. The development of clinical manifestations in female carriers is extremely rare. (2) Identification of female carriers requires either prior identification of the disease-causing mutation in the family or, if an affected male is not available for testing, sequence analysis. If sequence analysis results are negative, deletion/duplication analysis should be performed to identify heterozygous exonic, multiple exonic, or whole-gene deletions that are not detectable by sequence analysis in carrier females. Carrier testing for relatives at risk for autosomal recessive dyskeratosis congenita (caused by mutations in CTC1, TERT, WRAP53, NHP2, or NOP10) requires prior identification of the disease-causing mutations in the family. Note: Heterozygotes for these autosomal recessive disorders may not be at increased risk of developing the disorder. However, mutations in TERT can cause both autosomal dominant and autosomal recessive DC; the effect of heterozygosity for one mutant TERT allele in individuals from families with autosomal recessive DC mutations is not known.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family or, if a mutation is not identified in an affected family member, documentation of short telomere length in an affected relative. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies for most known types of DC require prior identification of the disease-causing mutation(s) in the family. Genetically Related (Allelic) DisordersAcquired aplastic anemia has been associated with germline mutations in TERC and TERT [Yamaguchi et al 2003, Yamaguchi et al 2005]. Some persons with apparently acquired aplastic anemia may actually have undiagnosed DC or a milder form of this telomere biology disorder.Idiopathic pulmonary fibrosis has been associated with mutations and single-nucleotide polymorphisms in TERT and TERC [Armanios et al 2007, Tsakiri et al 2007, Alder et al 2008]. This is also a telomere biology disorder closely related to DC (See Primary Pulmonary Fibrosis.) Liver cirrhosis associated with germline mutations in TERT or TERC has been reported in up to 7% of affected individuals [Calado et al 2011, Hartmann et al 2011].Cerebrobretinal microangiopathy with calcifications and cysts (CRMCC) or Coats Plus syndrome (OMIM 612199) is associated with compound heterozygous mutations in CTC1. Many features of these related disorders overlap with those of DC. These features include hair skin and nail changes, anemia, thrombocytopenia, osteopenia, intracranial calcifications, exudative retinopathy, and developmental delay. Individuals with CTC1 mutations have very short telomeres.All of these disorders overlap clinically with features of DC and appear to be part of the spectrum of telomere biology disorders, of which classic DC is the most severe [Armanios 2009, Savage & Bertuch 2010, Savage 2012].}

Natural History Classic Dyskeratosis Congenita (DC)The classic triad of abnormal fingernails and toenails, lacy, reticular pigmentation of the neck and upper chest, and oral leukoplakia is diagnostic (Figure 1); however, these features are not present in all individuals with DC and may or may not develop over time after the appearance of other complications listed below [Savage & Bertuch 2010, Dokal 2011]. The time of onset for these medical problems varies among individuals and thus the manifestations of DC do not progress in a predictable pattern. The spectrum ranges from individuals who develop bone marrow failure (BMF) first, and then years later develop other classic findings such as nail abnormalities, to others who have severe nail problems and abnormalities of skin pigmentation but normal bone marrow function. Dermatologic. Lacy, reticular pigmentation primarily of the neck and chest may be subtle or diffuse hyper- or hypopigmentation. Changes in skin pigmentation may become more pronounced with age. People with DC may lose dermatoglyphics with age.Dysplastic fingernails and toenails may worsen significantly over time and nails may eventually “disappear.”Hyperhidrosis is noted in some individuals. Growth and development. Short stature has been reported but height is variable.Intrauterine growth retardation has been noted in children with the more severe Hoyeraal Hreidarsson syndrome or Revesz syndrome variants.Developmental delay may be present in some. It can be more pronounced in persons with the Hoyeraal Hreidarsson syndrome or Revesz syndrome variants.Ophthalmic. Epiphora caused by stenosis of the lacrimal drainage system can result in blepharitis.Abnormal eyelash growth includes sparse eyelashes, ectropion, entropion, and trichiasis, which can lead to corneal abrasions, scarring, or infection if not treated.Bilateral exudative retinopathy seen in the Revesz syndrome variant can lead to blindness.Dental. Dental caries and periodontal disease had been reported to occur at early ages and at higher rates than in the general population; however, they may currently be less frequent because of improved dental hygiene.Decreased root/crown ratio is attributed to abnormal tooth development.Taurodontism (enlarged pulp chambers of the teeth) may be noted on dental x-ray.Ears, nose, and throat. Oral leukoplakia is part of the diagnostic triad. It may be a presenting sign found in childhood or it may develop over time.Deafness has been reported but is rare.Squamous cell carcinoma of the head and neck. Persons with DC are at very high risk for these cancers.Cardiovascular. Rare reported congenital heart defects include atrial and ventricular septal defects, myocardial fibrosis, and dilated cardiomyopathy.Respiratory. Pulmonary fibrosis may be a presenting sign or may develop over time. Pulmonary fibrosis is manifest as bibasilar reticular abnormalities, ground glass opacities, or diffuse nodular lesions on high-resolution computed tomography and abnormal pulmonary function studies that include evidence of restriction (reduced vital capacity with an increase in FEV1/FVC ratio) and/or impaired gas exchange (increased P_(A-a)O₂ with rest or exercise or decreased diffusion capacity of the lung for carbon monoxide). Gastrointestinal. Esophageal stenosis has been reported in several persons with DC and may worsen over time.Enteropathy, which may result in poor growth, has been reported.Liver fibrosis is a potential complication that has been noted and may occur at variable rates.Hepatopulmonary syndrome has been reported.Elevated risk of anorectal adenocarcinomas has been reported in DC. Genitourinary. Urethral stenosis in males may be present at diagnosis or develop over time.Elevated risk of cervical squamous cell cancer has been reported in DC. Musculoskeletal. Osteoporosis and osteopenia have been reported. The contribution of prior treatment and co-morbid conditions to these complications is not known.Avascular necrosis of the hips and shoulders can result in pain and reduced function. Several individuals have required hip replacement surgery at young ages. Neurologic. Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the Hoyeraal Hreidarsson syndrome and Revesz syndrome variants. Cerebellar hypoplasia is present in the Hoyeraal Hreidarsson syndrome variant (Figure 3) and intracranial calcifications of unknown significance have been reported in the Revesz syndrome variant. In addition, microcephaly has been reported in some persons with DC.FigureFigure 3. MRI of cerebellar hypoplasia in an individual with the Hoyeraal Hreidarsson variant of dyskeratosis congenita. Arrow indicates the hypoplastic cerebellum. Psychiatric. Schizophrenia has been reported in two persons. A small study of six children and eight adults with DC found higher than expected rates of neuropsychiatric complications. However, the true prevalence of disorders such as depression and bipolar disorder in individuals with CD is unknown [Rackley et al 2012]. Endocrine. Hypogonadism has been noted in a small number of severely affected males. Hematologic. Bone marrow failure is a common presenting sign and may progress over time. Individuals with DC are at increased risk for leukemia (see Cancer).Immunologic. Immunodeficiency of variable severity has been reported in DC. It has not been fully characterized, but it appears that some individuals may have reduced numbers of B-cells, T-cells, and/or NK cells.Cancer. Persons with DC are at high risk for leukemia and squamous cell cancer of the head and neck or anogenital region. The first study to quantify these risks evaluated reports of cancer in persons with DC from the DC cohort study at the National Cancer Institute (NCI) and from the scientific literature [Alter et al 2009]. The median age of onset for all cancers was 37 years (range 25-44 years) in the NCI cohort and 29 years (range 19-70 years) in the literature cases. The most frequent solid tumors were head and neck squamous cell carcinomas (40% in both groups), followed by skin and anorectal cancer. In the NCI cohort, the ratio of observed to expected (O/E) cancers was 11-fold greater in persons with DC compared to the general population. The highest O/E ratios were for tongue cancer (1154-fold increase) and acute myeloid leukemia (AML) (195-fold increase). Myelodysplastic syndrome (MDS) also occurs at increased rates in persons with DC [Alter et al 2009]. In this study, the median age of MDS was 35 years (range 19-61 years) and the O/E ratio of MDS was 2362-fold that of the general population.Severe Forms of DCHoyeraal Hreidarsson syndrome, a very severe form of DC, presents in early childhood [Walne & Dokal 2008]. In addition to features of DC, cerebellar hypoplasia is required to establish the diagnosis (Figure 3). The findings in the original cases included cerebellar hypoplasia, developmental delay, immunodeficiency, intrauterine growth retardation, and BMF, as well as the DC diagnostic triad [Hoyeraal et al 1970]. Revesz syndrome has many of the features of DC and presents in early childhood [Revesz et al 1992]. In addition to features of DC, bilateral exudative retinopathy is required to establish the diagnosis. The original cases included individuals with intracranial calcifications, intrauterine growth retardation, BMF, and sparse, fine hair in addition to nail dystrophy and oral leukoplakia.

Genotype-Phenotype Correlations Genotype-phenotype correlations have not yet been studied comprehensively. In general, persons with DKC1 and TINF2 mutations appear to have more clinical features and complications than persons with mutation of the other genes known to cause DC [Alter et al 2012]. Persons with DKC1 or TINF2 mutations may have Hoyeraal Hreidarsson syndrome. Persons with Revesz syndrome may have TINF2 mutations. Some individuals with TINF2 mutations developed bone marrow failure manifest as aplastic anemia by age ten years; others may be silent carriers [Walne et al 2008, Savage & Bertuch 2010].Individuals with Hoyeraal Hreidarsson and Revesz syndrome have shorter telomeres than individuals with classic DC.Persons with autosomal dominant, heterozygous TERT mutations may present as adults with isolated bone marrow failure or isolated pulmonary fibrosis, and thus may be the least affected of all those with DC. Individuals with autosomal recessive TERT mutations may have the severe phenotype Hoyeraal Hreidarsson syndrome.Those with TERC mutations appear to have variability in severity. Some individuals with TERC mutations may present with isolated bone marrow failure rather than the classic mucocutaneous features seen with, for example, DKC1 mutations. Individuals with DC who do not have a mutation in one of the seven known genes often have the most clinically severe phenotypes, including multiple features of DC, Hoyeraal Hreisdarsson syndrome, or Revesz syndrome [Alter et al 2012].The two individuals reported with WRAP53 compound heterozygous mutations had classic DC with the mucocutaneous phenotype and bone marrow failure. One of these individuals also had tongue squamous cell cancer.Persons with CTC1 mutations may not have the mucocutaneous triad but often do have cytopenias, retinal exudates, intracranial calcifications or cysts, ataxia, IUGR, osteopenia, and/or poor bone healing.

Differential Diagnosis Dyskeratosis congenita (DC) can be challenging to diagnose because of its clinical heterogeneity. DC should be considered as a possible cause of bone marrow failure (BMF) in persons in whom Fanconi anemia has been excluded based on normal chromosome breakage studies with diepoxybutane (DEB) or mitomycin C (MMC).Head/neck or anogenital cancer may be the first manifestation of DC in persons younger than age 50 years who do not have other risk factors or BMF.BMF may be the first manifestation of DC in individuals of any age. Telomere length testing should be performed if chromosome breakage is normal.It should be noted that telomere length studied in individuals with Fanconi anemia, Diamond-Blackfan anemia, and Shwachman Diamond syndrome is typically greater than the first percentile for age [Alter et al 2007].Disorders with clinical features that overlap those of DC include the following. Disorders with nail dysplasiaNail-patella syndromeTwenty-nail dystrophy (OMIM 161050)Keratoderma with nail dystrophy and motor-sensory neuropathy (OMIM 148360) Poikiloderma with neutropenia (OMIM 604173)Fanconi anemia (FA), characterized by physical abnormalities, bone marrow failure, and increased risk of malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. By age 40 to 48 years, the estimated cumulative incidence of bone marrow failure is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) 10%-33%; and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 28%-29%. The diagnosis of FA rests upon the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Mutations in one of at least 15 genes are causative. Mutations in the genes for all but one of the Fanconi anemia complementation groups are inherited in an autosomal recessive manner. FANCB mutations are inherited in an X-linked manner.Diamond-Blackfan anemia (DBA), in its classic form characterized by a profound isolated normochromic and usually macrocytic anemia with normal leukocytes and platelets; congenital malformations in 25%-50% of affected individuals; and growth retardation in 30%. The hematologic complications occur in 90% of affected individuals during the first year of life (median age of onset is two months). Eventually 40% of affected individuals are corticosteroid dependent, 40% are transfusion dependent, and 20% go into remission. The phenotypic spectrum ranges from a mild form (e.g., mild anemia; no anemia with only subtle erythroid abnormalities; physical malformations without anemia) to a severe form of fetal anemia resulting in non-immune hydrops fetalis. DBA is associated with an increased risk of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma. DBA has been associated with mutations in nine genes that encode ribosomal proteins. A mutation in one of these nine genes is identified in approximately 53% of individuals with DBA. DBA is inherited in an autosomal dominant manner; approximately 55%-60% of affected individuals have a de novo mutation.Shwachman Diamond syndrome (SDS), characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure, hematologic abnormalities with single- or multi-lineage cytopenia and susceptibility to myelodysplasia syndrome (MDS) and acute myelogeneous leukemia (AML), and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common. The diagnosis of SDS relies on clinical findings, including pancreatic dysfunction and characteristic hematologic problems. SBDS is the only gene currently known to be associated with SDS and biallelic mutations are found in more than 90% of cases. Inheritance is autosomal recessive.Acquired aplastic anemia, characterized by tri-lineage bone marrow cytopenias [Young et al 2008]. It is often progressive and may occur at any age. Telomere length testing helps identify the subset of individuals with later onset aplastic anemia who have a telomere biology disorder; these individuals may have a few or none of the other clinical findings of DC. Other known causes of aplastic anemia include an immune process, infection, or drug reaction. In many individuals the cause of acquired aplastic anemia is unknown.Idiopathic pulmonary fibrosis (IPF), the most frequent idiopathic interstitial pneumonia. It results in progressive fibrotic lung disease and has high morbidity and mortality. Persons with DC may develop IPF and it is conceivable that IPF in a young person could be the first manifestation of DC and, thus, DC should be considered in young persons with IPF. In some individuals, IPF, like aplastic anemia, may be a manifestation of a telomere biology disorder. See Familial Pulmonary Fibrosis.Coats plus syndrome (OMIM 612199), an autosomal recessive disorder characterized by the presence of intracranial calcifications, leukodystrophy, retinal telangiectasia and retinal exudates. Affected individuals may also have osteopenia with poor bone healing, and vascular ectasias of the stomach, small intestine, and liver. Some individuals with Coats plus have hair, skin, and nail findings similar to those seen in DC. Anemia has also been reported. The retinal findings and intracranial classifications are similar to those seen in Revesz syndrome. Coats plus is caused by autosomal recessive mutations in an important telomere biology gene, CTC1 [Polvi et al 2012, Savage 2012, Anderson et al 2012] (Figure 2).Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).X-linked DC (Hoyeraal Hreidarsson syndrome)Autosomal dominant DC (Revesz syndrome)Autosomal recessive DC

Management Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with dyskeratosis congenita (DC), it is important to note that the clinical spectrum of DC is broad and signs and symptoms develop at various ages and rates. Suggested studies to consider include:Dermatologic. Thorough skin and nail examinationGrowth and development evaluationOphthalmic. Thorough examination for complications related to lacrimal duct stenosis, abnormal eyelash growth, and retinal disorders including exudative retinopathyDental. Baseline evaluation for oral hygiene, leukoplakia, and oral squamous cell cancer Otolaryngology. Baseline evaluation for leukoplakia and squamous cell head/neck cancer Gastrointestinal and hepatic. History of potential swallowing difficulties and/or enteropathy; baseline liver function testsGenitourinary. For males, assessment for urethral stenosisMusculoskeletal. Consideration of baseline bone mineral density scan; history of any joint problemsNeurologic. If early-onset neurologic findings (e.g., ataxia) or many of the complications listed above are present, consideration of brain MRI to evaluate for cerebellar hypoplasia or intracranial calcificationsBone marrow failure (BMF)Evaluation by a hematologist to determine if signs of BMF are present. Evaluation may include complete blood count and bone marrow aspiration and biopsy.Consider HLA typing of the affected individual, sibs, and parents in anticipation of possible need for hematopoietic stem cell transplantation (HSCT)Pulmonary fibrosisBaseline pulmonary function tests (PFTs) including carbon monoxide diffusion capacityEvaluation by a pulmonologist if the individual is symptomatic or PFTs are abnormalSmoking cessation, if applicableIncreased risk of cancerEvaluation by an otolaryngologist and dentist as soon as the individual is able to cooperate with the examinationGynecologic examination for females starting by age 16 years or when sexually activeGenetics consultationTreatment of ManifestationsThe specific treatment for DC-related complications must be tailored to the individual [Savage & Alter 2009, Savage et al 2009]. The recommendations below were discussed at the first DC clinical research workshop in 2008 [Savage et al 2009] but because of the rarity of DC are not based on large-scale clinical trials. Affected individuals may have few or many of the complications associated with DC. Comprehensive coordinated care among specialties is required.Bone marrow failure (BMF). Following the model of the Fanconi anemia consensus guidelines [Eiler et al 2008], treatment of BMF is recommended if the hemoglobin is consistently below 8 g/dL, platelets lower than 30,000/mm³, and neutrophils below 1000/mm³. If a matched-related donor is available, HSCT should be the first consideration for treatment for hematologic problems such as BMF or leukemia regardless of age. HSCT from an unrelated donor can be considered, although a trial of androgen therapy (e.g., oxymetholone or danazol) may be considered first. Persons with DC may be more sensitive to androgens than individuals with Fanconi anemia, and the dose must be adjusted to reduce side effects such as impaired liver function, virilization, or behavioral problems (e.g., aggression, mood swings). The suggested starting dose of oxymetholone is 0.5 to 1 mg/kg/day, half the dose used in Fanconi anemia. It may take two to three months at a constant dose to see a hematologic response. Side effects, including liver enzyme abnormalities, need to be monitored carefully. Baseline and follow-up liver ultrasound examinations should be performed for individuals receiving androgen therapy because of the possibility of liver adenomas and carcinomas, which have been reported in Fanconi anemia and in persons using androgens for benign hematologic diseases or for non-hematologic disorders [Velazquez & Alter 2004].Hematopoietic growth factors may be useful in BMF. However, splenic peliosis and splenic rupture have been reported in two individuals with DC receiving androgens and G-CSF [Giri et al 2007]. G-CSF with erythropoietin has occasionally been useful but perhaps should also not be used in combination with androgens. HSCT is the only curative treatment for severe BMF or leukemia in DC. It should be performed at centers experienced in treating DC. Reported problems include graft failure, graft-versus-host disease (GVHD), sepsis, pulmonary fibrosis, hepatic cirrhosis, and veno-occlusive disease [Berthou et al 1991, de la Fuente & Dokal 2007] that is caused in part by underlying pulmonary and liver disease [Yabe et al 1997, Dror et al 2003, Brazzola et al 2005, de la Fuente & Dokal 2007, Ostronoff et al 2007]. As a result, long-term survival of persons with DC following HSCT has been poor. Reduced-intensity preparative regimens being studied in a few institutions may improve long-term outcomes [Dietz et al 2011, Nishio et al 2011, Vuong et al 2010].The range of clinical phenotypes seen in DC and the possibility of non-manifesting or very mildly affected heterozygotes within families may complicate the selection of related HSCT donors [Fogarty et al 2003, Denny et al 2008]. Potential related HSCT donors should be tested either for the mutation present in the proband or, if the mutation is not known, for telomere length.Cancer. Specific treatment should be tailored to the type of cancer.Affected individuals undergoing chemotherapy for cancer may have increased risk for prolonged cytopenias as a result of underlying BMF. This risk has not been quantitated; studies are ongoing. Individuals with DC may be at increased risk of therapy-related pulmonary and hepatic toxicity. Pulmonary function tests and liver function should be monitored carefully.Long-term data on the effects of cancer radiotherapy in DC are not available. Affected individuals may be at increased risk for radiotherapy-related complications based on observations in persons undergoing radiotherapy in HSCT.Although the risk of MDS is high in DC, many persons have abnormal cytogenetic clones and/or morphologic changes consistent with abnormal myelopoiesis but may not have severe cytopenias.Pulmonary fibrosis. The options for therapy in persons with DC and pulmonary fibrosis are primarily supportive care. Lung transplantation may be considered in severe cases. (See Familial Pulmonary Fibrosis.)SurveillanceThe recommendations below were discussed at the first DC clinical research workshop in 2008 [Savage et al 2009] but because of the rarity of DC are not based on large-scale clinical trials. Most of the recommendations are modeled after the Fanconi anemia consensus guidelines [Eiler et al 2008].Bone marrow failure Consider repeating a complete blood count (CBC) once a year if CBCs are normal. CBCs should be obtained more frequently at the discretion of the treating hematologist. Consider annual bone marrow aspirate and biopsy that includes morphologic examination and cytogenetic studies.Patients on androgen therapy for bone marrow failure Check liver function tests prior to starting and then every three months. Perform liver ultrasound examination semiannually for adenomas. Check cholesterol and triglycerides prior to starting and every six months.Cancer surveillance. Most solid tumors develop after the first decade (median onset is age 28 years).Monthly self-examination for oral, head, and neck cancerAnnual cancer screening by an otolaryngologistAnnual gynecologic examinationAnnual skin cancer screening by a dermatologistPulmonary fibrosis. Perform annual pulmonary function tests starting either at diagnosis or at an age when the patient is able to appropriately perform the test (typically age ~8 years).Oral and dental surveillanceSchedule routine screening and dental hygiene visits every six months. Maintain good oral hygiene. The patient’s dentist should be made aware of the increased risk of head and neck squamous cell cancers and perform a thorough examination at each visit. Oral leukoplakia should be monitored carefully and suspicious lesions should be biopsied.Agents/Circumstances to AvoidBlood transfusionsTransfusions of red cells or platelets should be avoided or minimized for those who are candidates for HSCT.To minimize the chances of sensitization, family members must not act as blood donors if HSCT is being considered.All blood products should be leukodepleted and irradiated.Radiation. It is prudent to minimize exposure to therapeutic radiation since data on radiation side effects are limited.Androgens and growth factors. The combination of androgens and G-CSF was associated with splenic peliosis and rupture in two individuals; thus, the combination should be avoided [Giri et al 2007].Cancer prevention. Given the increased susceptibility of individuals with DC to developing leukemias and other malignancies, individuals with DC are advised to avoid toxic agents that have been implicated in tumorigenesis, including smoking.Evaluation of Relatives at RiskIf a relative has signs or symptoms suggestive of DC or is being evaluated as a potential HSCT donor, telomere length testing is warranted or molecular genetic testing if the disease-causing mutation(s) in the family are known.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationStudies of the effectiveness of danazol, a modified testosterone, are underway in DC and the related telomere biology disorders. Danazol may have fewer side effects than oxymetholone. The response and optimal dosing in DC is not yet defined.DC-specific HSCT studies are ongoing at several institutions.Studies to improve the clinical and molecular characterization of DC are underway at the National Cancer Institute (marrowfailure.cancer.gov).Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular Genetics Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Dyskeratosis Congenita: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDKC1Xq28H/ACA ribonucleoprotein complex subunit 4DKC1 @ LOVD
Resource of Asian Primary Immunodeficiency Diseases (RAPID)
Telomerase DatabaseDKC1TERC3q26​.2Not applicableTelomerase Database, TR mutationsTERCTERT5p15​.33Telomerase reverse transcriptaseTelomerase Database
TERT homepage - Mendelian genesTERTTINF214q12TERF1-interacting nuclear factor 2Telomerase Database, TINF2 mutations
TINF2 homepage - Mendelian genesTINF2NOP1015q14H/ACA ribonucleoprotein complex subunit 3Telomerase Database, Nola3 (Nop10) mutations
NOP10 homepage - Mendelian genesNOP10NHP25q35​.3H/ACA ribonucleoprotein complex subunit 2Telomerase Database, Nola2 (NHP2) mutations
NHP2 homepage - Mendelian genesNHP2WRAP5317p13​.1Telomerase Cajal body protein 1Telomerase DatabaseWRAP53Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Dyskeratosis Congenita (View All in OMIM) View in own window 127550DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT, 1; DKCA1 187270TELOMERASE REVERSE TRANSCRIPTASE; TERT 224230DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE, 1; DKCB1 300126DYSKERIN; DKC1 305000DYSKERATOSIS CONGENITA, X-LINKED; DKCX 602322TELOMERASE RNA COMPONENT; TERC 604319TRF1-INTERACTING NUCLEAR FACTOR 2; TINF2 606470NUCLEOLAR PROTEIN FAMILY A, MEMBER 2; NOLA2 606471NUCLEOLAR PROTEIN FAMILY A, MEMBER 3; NOLA3 612661WD REPEAT-CONTAINING PROTEIN ANTISENSE TO TP53; WRAP53 613988DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE, 3; DKCB3Molecular Genetic Pathogenesis Dyskeratosis congenita (DC) is thought to be a disorder of telomere biology. The telomere is a complex structure (Figure 2). The TTAGGG nucleotide repeats at the chromosome end fold back to create a t-loop. Many proteins bind to the t-loop and others bind to those proteins to form a stable telomere “cap.” Seven different genes (DKC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53) encoding critical components of the telomere have been found to be mutated in individuals with DC.The proteins encoded by DKC1, NHP2, and NOP10 are members of the H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family, which is involved in various aspects of rRNA processing and modification [Walne & Dokal 2008]. The proteins encoded by the genes DKC1, NHP2, and NOP10 localize to the dense fibrillar components of nucleoli and to coiled (Cajal) bodies in the nucleus. Both 18S rRNA production and rRNA pseudouridylation are impaired if any one of the four proteins is depleted. These H/ACA snoRNP proteins are also components of the telomerase complex. Telomerase (TERT) is a reverse transcriptase which uses its RNA component, TERC, to add the TTAGGG nucleotide repeats to the chromosome ends. WRAP53 (TCAB1) is required for the transport of telomerase to Cajal bodies for assembly of the holoenzyme complex. TINF2 encodes the TIN2 protein, which is a part of the shelterin telomere protection complex (reviewed in Palm & de Lange [2008]). Shelterin consists of six proteins encoded by the genes TINF2, TERF1, TERF2, POT1, ACD (TPP1), and TERF2IP (RAP1). TERF1 (TRF1), TERF2 (TRF2), POT1, and ACD (TPP1) proteins bind to the telomeric DNA and their interactions with TIN2 and TERF2IP (RAP1) create a stable complex.The CST complex is an essential telomeric capping complex that consists of CTC1 (encoded by CTC1), STN1 (OBFC1), and TEN1 (TEN1) [Miyake et al 2009; Surovtseva et al 2009]. This complex is proposed to promote efficient priming of telomeric C-strand synthesis. Figure 2 shows some of these interactions. DKC1Normal allelic variants. DKC1 comprises 15 exons and spans a genomic region of 15,734 base pairs.Pathologic allelic variants. More than 40 pathologic allelic variants are described for DKC1; the majority are missense mutations that change the amino acid residue. See Table 2.Table 2. Selected DKC1 Pathologic Allelic Variants View in own windowDNA Nucleotide Change Protein Amino Acid Change Reference SequencesLiterature Referencec.-142C>G-- NM_001363​.3
NP_001354​.1Walne & Dokal [2004]c.5C>Tp.Ala2ValDokal & Vulliamy [2003]c.29C>Tp.Pro10LeuMarrone et al [2005]c.91C>Gp.Gln31Gluc.91C>Ap.Gln31LysVulliamy et al [2006]c.106T>Gp.Phe36ValHeiss et al [1998]c.109_111delCTTp.Leu37delc.113T>Cp.Ile38ThrDokal & Vulliamy [2003]c.115A>Gp.Lys39Gluc.119C>Gp.Pro40ArgHeiss et al [1998]c.121G>Ap.Glu41LysDokal & Vulliamy [2003]c.127A>Gp.Lys43Gluc.146C>Tp.Thr49MetKnight et al [1999a]c.194G>Cp.Arg65ThrDokal & Vulliamy [2003]c.196A>Gp.Thr66Alac.200C>Tp.Thr67IleMarrone et al [2005]c.204C>Ap.His68Glnc.361A>Gp.Ser121GlyKnight et al [1999a]c.472C>Tp.Arg158TrpKnight et al [2001]c.838A>Cp.Ser280Argc.911G>Ap.Ser304AsnDu et al [2009b] c.949C>Tp.Leu317PheDokal & Vulliamy [2003]c.941A>Gp.Lys314ArgMarrone et al [2005]c.949C>Tp.Leu317Phec.949C>Gp.Leu317ValDu et al [2009b]c.961C>Gp.Leu321ValDokal & Vulliamy [2003]c.965G>Ap.Arg322Glnc.1049T>Cp.Met350ThrKnight et al [2001]c.1050G>Ap.Met350IleDokal & Vulliamy [2003]c.1058C>Tp.Ala353ValKnight et al [2001]c.1075G>Ap.Asp359AsnMarrone et al [2005]c.1150C>Tp.Pro384SerDokal & Vulliamy [2003]c.1151C>Tp.Pro384LeuKnight et al [2001]c.1156G>Ap.Ala386ThrMarrone et al [2005]c.1193T>Cp.Leu398ProDokal & Vulliamy [2003]c.1205G>Ap.Gly402GluHeiss et al [1998]c.1204G>Ap.Gly402ArgDokal & Vulliamy [2003]c.1223C>Tp.Thr408IleMarrone et al [2005]c.1226C>Tp.Pro409Leuc.1205G>Ap.Gly402GluKirwan et al [2008]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. The primary transcript of DKC1 (isoform 1, NP_001354.1) encodes a protein of 514 amino acids. Isoform 2 uses an alternate in-frame splice site in the 3' coding region, compared to variant 1, resulting in a shorter isoform of 509 amino acids (reference sequence NP_001135935.1). Dyskerin plays multiple roles in human cells. It binds H/ACA and telomerase RNAs (TERC) via its PUA domain. It also functions in ribosomal (r)RNA processing, ribosomal subunit assembly, and centromere and microtubule binding. Abnormal gene product. Most disease causing mutations in DKC1 occur in the PUA domain, suggesting that DC arises from abnormal RNA binding.TERCNormal allelic variants. TERC is a non-coding RNA of 451 bp comprising one exon. Pathologic allelic variants. See Table 3.Table 3. Selected TERC Pathologic Allelic Variants View in own windowRNA Nucleotide Change
(Alias ¹) Reference SequencesLiterature Reference ^{2r.-240delctNR_001566​.1Field et al [2006](C-99G) 3Keith et al [2004] r.2g>c
(G2C)Marrone et al [2007a]Contiguous gene deletion 4(1- 316)Vulliamy et al [2004]r.21c>uFogarty et al [2003]r.28_34del7
(28-34)Xin et al [2007]r.35c>uDu et al [2009b]r.37a>g
(A37G)Vulliamy et al [2006]r.48a>g
(A48G)Vulliamy et al [2006]r.52_55delcuaaVulliamy et al [2006]r.53_87del35Marrone et al [2007a]r.58g>a
(G58A)Dokal & Vulliamy [2003]r.72c>gDokal & Vulliamy [2003]r.79delcVulliamy et al [2006]r.96-97delcuVulliamy et al [2004]r.98g>a
(G98A)Calado & Young [2008]r.100u>a
(T100A)Du et al [2009b]c.110_113delgactWalne & Dokal [2004]c.107_108gc>agVulliamy et al [2001]r.116c>u
(C116T)Walne & Dokal [2004]r.117a>c
(A117C)Ly et al [2005]r.143g>a
(G143A)Vulliamy et al [2004]r.178g>a
(G178A)Marrone et al [2007a]r.180c>u
(C180T)Marrone et al [2007a]r.204c>g
(C204G)Fogarty et al [2003]r.216_229del14
(Del 216-229)Vulliamy et al [2006] r.228G>A
(G228A)Walne & Dokal [2004]r.305g>a
(G305A)Fogarty et al [2003]r.322g>a
(G322A)Fogarty et al [2003]r.323c>u
(C323T)Calado & Young [2008](del 378 through 3’ end of TERC)Vulliamy et al [2004]r.378_415del38Dokal & Vulliamy [2003]r.391_392delcc
(389-390)Ly et al [2005] r.408c>gVulliamy et al [2001]r.408c>aMarrone et al [2005]r.410c>gVulliamy et al [2001]r.450g>aWalne & Dokal [2004](16u>c, 16bp downstream of 3’ transcript of TERC)Fogarty et al [2003](821-bp deletion including 3' end of TERC)Vulliamy et al [2001]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). For this gene: the prefix "r." is used to indicate that a change is described at RNA level; numbering is relative to the transcription start site; nucleotides are designated by the bases (in lower case); bases are a (adenine), c (cytosine), g (guanine), and u (uracil).1. Variant designation that does not conform to current naming conventions2. First literature reference given when possible3. Promoter mutation in a patient with paroxysmal nocturnal hemoglobinuria4. Deletion of 2980 bp extending from nucleotide 835 in the 3’ UTR of ACTRT3 (ARPM1), through the intergenic and TERC promoter sequences, to nucleotide 316 of TERC.Normal gene product. TERC encodes a non-coding RNA; no protein product is made. It serves as the RNA template for telomerase, the reverse transcriptase which adds nucleotide repeats to the telomere.Abnormal gene product. Not applicableTERTNormal allelic variants. TERT comprises 16 exons. NM_198253.2 is a transcript of 4018 nucleotides.Pathologic allelic variants. See Table 4.Table 4. Selected TERT Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias 1) Protein Amino Acid Change DisorderReference SequencesLiterature ReferenceNormalc.915G>Ap.Ala305Ala Normal variantNM_198253​.2
NP_937983​.2Vulliamy et al [2005]c.2097 C>T p.Ala699Ala Normal variantVulliamy et al [2005],
Yamaguchi et al [2005]c.2178 G>A p.Thr726Thr Normal variantVulliamy et al [2005],
Yamaguchi et al [2005] c.3039 C>Tp.His1013His Normal variantVulliamy et al [2005],
Yamaguchi et al [2005]Pathologicc.97C>Tp.Pro33SerIdiopathic pulmonary fibrosisTsakiri et al [2007]c.164T>Ap.Leu55GlnIdiopathic pulmonary fibrosisc.164T>Ap.Leu55GlnIdiopathic pulmonary fibrosisArmanios et al [2007]p.112delCp.Leu38Trpfs*40Idiopathic pulmonary fibrosisArmanios et al [2007]c.430G>Ap.Val144MetIdiopathic pulmonary fibrosisTsakiri et al [2007]c.604G>Ap.Ala202ThrAplastic anemiaYamaguchi et al [2005]c.835G>Ap.Ala279ThrDyskeratosis congenita / aplastic anemia Vulliamy et al [2005]c.1234C>Tp.His412TyrAplastic anemiaYamaguchi et al [2005]c.1378_1380delCAGp.441Gludel Normal variantYamaguchi et al [2005]c.1456C>Tp.Arg486CysIdiopathic pulmonary fibrosisTsakiri et al [2007]c. 1710(G>T;G>C) 2p.Lys570AsnDyskeratosis congenitaXin et al [2007]c.1892G>Ap.Arg631GlnThrombocytopenia/
pulmonary fibrosisKirwan et al [2008]c.2045G>Ap.Gly682AspDyskeratosis congenitaXin et al [2007]c.2029G>Tp.Gly677CysDyskeratosis congenita/ aplastic anemiaYamaguchi et al [2005]c.2080G>Ap.Val694MetAplastic anemiaYamaguchi et al [2005]c.2110C>Tp.Pro704SerDyskeratosis congenitaDu et al [2009b]c.2147C>Tp.Ala716ValAplastic anemiaDu et al [2009b]c.2162C>Gp.Pro721ArgDyskeratosis congenitaVulliamy et al [2006]c.2177C>Tp.Thr726MetDyskeratosis congenitaXin et al [2007]c.2240delTp.Val747Alafs*20Idiopathic pulmonary fibrosisTsakiri et al [2007]c.2315A>Gp.Tyr772CysIdiopathic AAYamaguchi et al [2005]c.2431C>Tp.Arg811CysAutosomal recessive DCMarrone et al [2007b]c.2537A>Gp.Tyr846CysAplastic anemiaDu et al [2009b]c.259G>Ap.Arg865HisIdiopathic pulmonary fibrosisTsakiri et al [2007]c.2628C>Gp.His876GlnAplastic anemiaDu et al [2008]c.2701C>Tp.Arg901TrpAutosomal recessive DCMarrone et al [2007b]c.2706G>Cp.Lys902AsnDyskeratosis congenitaArmanios et al [2007]c.2935C>Tp.Arg979TrpDyskeratosis congenitaVulliamy et al [2005],
Savage et al [2006]c.3329C>Tp.Thr1110MetIdiopathic pulmonary fibrosisArmanios et al [2007]c.3043T>Cp.Cys1015ArgAplastic anemiaDu et al [2009b]c.3184G>Ap.Ala1062ThrAplastic anemiaYamaguchi et al [2005]c.3268G>Ap.Val1090MetAplastic anemia Yamaguchi et al [2005]c.3404_3580del177
(3346_3522del) Idiopathic pulmonary fibrosisTsakiri et al [2007]c.219+1G>A
(IVS1+1G>A)--Usual interstitial pneumonia Armanios et al [2007]c.2613-2A>G
(IVS9-2 A>C)--Idiopathic interstitial pneumonia Armanios et al [2007]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Uncertainty of nucleotide change in parenthesisNormal gene product. The telomerase protein comprises 1132 amino acids. Telomerase is a ribonucleoprotein polymerase (reverse transcriptase) that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity encoded by this gene and an RNA component that serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis [Armanios 2009].Abnormal gene product. Mutations in telomerase that are associated with DC, IPF, or aplastic anemia typically result in loss or reduced expression of the enzyme.TINF2Normal allelic variants. TINF2 comprises nine exons (isoform 2, NM_012461.2). An alternative isoform consists primarily of the first six exons (NM_001099274.1). NM_001099274.1 is a transcript of 1869 base pairs.The contribution of these alternative isoforms to human disease is not yet known. Pathologic allelic variants. All of the TINF2 mutations described to date have been located in exon 6. It is not yet known if mutations elsewhere in the gene cause disease. See Table 5.Table 5. Selected TINF2 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias 1)Protein Amino Acid Change
(Alias 1) Reference SequencesLiterature Referencec.805C>Tp.Gln269XNM_001099274​.1
NP_001092744​.1Sasa et al [2012]c.811C>Tp.Gln271XSasa et al [2012](Ex6+234A>G)(Lys280Glu) 2Savage et al [2008]c.838A>Tp.Lys280XWalne et al [2008]
Sasa et al [2012]c.839delAp.Lys280Argfs*37
(K280Rfs*36)c.844C>Tp.Arg282Cys(Ex6+240C>A)(Arg282Ser) 2Savage et al [2008]c.847C>Tp.Pro283SerWalne et al [2008]c.847C>Gp.Pro283Alac.848C>Ap.Pro283Hisc.850A>Gp.Thr284Alac.849dupC
(849_850insC)p.Thr284Hisfs*8c.860T>Cp.Leu287Proc.862T>Cp.Phe288Leu 3Du et al [2009a]c.865CC>AGp.Pro289SerWalne et al [2008]c.871A>Gp.Arg291Glyc.892delCp.Gln298Argfs*19c.706C>Tp.Pro236Ser 3c.734C>Ap.Ser245Tyr 3c.841G>Ap.Glu281Lys 3 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions 2. Predicted from in silico analyses identifying putative exonic splicing enhancers [Savage et al 2008]3. Patient with bone marrow failure onlyNormal gene product. TINF2 encodes the TIN2 protein, which is an important part of the shelterin telomere protection complex. TIN2 binds to TERF1 and TERF2, which bind directly to the telomeric DNA.Abnormal gene product. The functional consequences of TINF2 mutations are not yet known. They occur in a highly evolutionarily conserved region of the protein and are predicted to have significant effects on protein function. NHP2 (NOLA2) — Autosomal RecessiveNormal allelic variants. NHP2 has four exons. NM_017838.3 is transcript variant 1, comprising 867 nucleotides. An alternative isoform lacks exon 3 (NM_001034833.1).Pathologic allelic variants. All NHP2 mutations described to date are in exon 4. See Table 6.Table 6. Selected Pathologic Variants of NHP2 (NOLA2) — Autosomal RecessiveView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesLiterature Referencec.376 G>Ap.Val126MetNM_017838​.3
NP_060308​.1Vulliamy et al [2008]c.415 T>C 1p.Tyr139Hisc.460T>A 1p.*154Argext*51See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Compound heterozygous mutant alleles observed in one affected individualNormal gene product. The H/ACA ribonucleoprotein complex subunit 2 protein comprises 153 amino acids.Abnormal gene product. Mutations in NHP2 reported in two families resulted in reduced levels of TERC and shortened telomeres. NOP10 (NOLA3) — Autosomal RecessiveNormal allelic variants. NOP10 comprises two exons. The transcript has 552 base pairs.Pathologic allelic variants. One family with a NOP10 mutation has been described (see Table 7).Table 7. Selected Pathologic Variant of NOP10 (NOLA3) — Autosomal RecessiveView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequenceLiterature Referencec.100C>Tp.Arg34TrpNM_018648​.3
NP_061118​.1Walne et al [2007]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. NOP10 encodes an H/ACA ribonucleoprotein complex subunit 3 protein that comprises 64 amino acids. Abnormal gene product. The reported mutation resulted in reduced TERC levels and shortened telomeres.WRAP53 (TCAB1) Normal allelic variants. WRAP53 comprises ten exons. Alternatively spliced transcript variants that differ only in the 5' UTR have been found for the gene. NM_018081.2 is the longest transcript; other variants encode the same protein [provided by RefSeq, Mar 2011].Pathologic allelic variants. See Table 8.Table 8. Selected Pathologic Variants of WRAP53View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesLiterature Referencec.492C>Ap.Phe164LeuNM_018081​.2 NP_060551​.2Zhong et al [2011]c.1192C>Tp.Arg398Trpc.1126C>T p.His376Tyrc.1303G>Ap.Gly435ArgSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. WRAP53 encodes the TCAB1 protein, which is required for the transportation of telomerase to Cajal bodies in the nucleus for assembly of the telomerase ribonucleoprotein complex.Abnormal gene product. Compound heterozygous mutations in WRAP53 result in loss of its protein product, TCAB1, from Cajal bodies and mislocalization of telomerase.CTC1Normal allelic variants. CTC1 comprises 23 exons spanning 23,273 bp of genomic sequence on chromosome 17p13.1. The primary isoform results from the NM_025099.5 transcript. Pathologic allelic variants. CTC1 mutations reported include missense mutations and deletions causing a frameshift.Normal gene product.CTC1 is a 134.5-kd protein which consists of 1217 amino acids (NP_079375.3). The CTC1 protein is an essential component of the CST complex which is implicated in telomere protection and DNA metabolism. The human CST complex has only recently been defined.Abnormal gene product. Compound heterozygous mutations in CTC1 appear to result in short telomeres for age. CTC1 mutations reported include missense mutations and deletions causing a frameshift. The specific effect of the mutations on protein function is currently being studied.}