Dyskeratosis Congenita (DC) and Related Disorders Panel

Dyskeratosis congenita (DC) is a rare inherited disorder of telomere biology with multi-system abnormalities. DC is primarily characterized by the presence of at least two of the three cardinal phenotypic features of dysplastic fingernails and toenails, reticular skin pigmentation of the neck and upper chest, and oral leukoplakia (Vulliamy et al. 2006. PubMed ID: 16332973; Savage et al. 2010. PubMed ID: 21189492). In addition, patients with DC have increased risk for bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), solid tumors, and pulmonary fibrosis (Walne et al. 2007. PubMed ID: 17507419; Kirwan et al. 2008. PubMed ID: 18005359). Other minor findings in patients with DC include excessive watering of the eyes, inflammation of the eyelids, abnormal eyelashes, premature greying of hair, alopecia, dental abnormalities, short stature, microcephaly, developmental delay, hypogonadism, liver cirrhosis, and osteoporosis. A diagnosis of DC can also be considered in the presence of one of the three cardinal features and two or more minor features mentioned above (Vulliamy et al. 2006. PubMed ID: 16332973).

Although DC is a rare condition, the exact prevalence is unknown. To date, pathogenic variants in more than 400 families have been described (Human Gene Mutation Database). In a study of individuals with suspected inherited BMF, 33.7% of them were diagnosed with DC due to pathogenic variants in genes related to telomere function and maintenance (Bluteau et al. 2018. PubMed ID: 29146883). Approximately 18% and 1% of patients with familial pulmonary fibrosis have pathogenic variants in TERT and TERC respectively (Garcia. 2011. PubMed ID: 21543794). Approximately 80-90% of individuals affected with DC experience bone marrow failure by age 30 (Kirwan et al. 2008. PubMed ID: 18005359).

Age of onset and progression of DC may vary, with different symptoms appearing at different ages, even among individuals within the same family. For example, the median age of onset for pigmentary abnormalities is 8 years with a range from 1-15 years, whereas, for leukoplakia, the median age of onset is 7 years, with a range from 1-32 years. The median age of onset for leukemia and other solid tumors is 37 and 29 years amongst National Cancer Institute (NCI) and literature cohorts respectively. The observed number of cancers (O) among DC patients to expected number (E) in the general population calculated as the O/E ratio was 11-fold for all cancer sites in the NCI cohort, with very high ratios of 1154-fold for tongue cancer, 2663-fold for MDS, and 126-fold for AML (Alter et al. 2009. PubMed ID: 19282459).

Patients with DC who have minimal clinical findings with normal bone marrow function are at the mild end of the spectrum, while those at the severe end of the spectrum have these features along with bone marrow failure (Savage et al. 2016. PubMed ID: 20301779). Two severe forms of DC include the Hoyeraal Hreidarsson and Revesz syndromes (HHS and RS). Individuals with HHS present DC very early in childhood, including in utero, and also present with intrauterine growth retardation, microcephaly, developmental delay, BMF leading to immune deficiencies, and cerebellar hypoplasia (Walne et al. 2008. PubMed ID: 18054794). Individuals with RS present with intrauterine growth retardation, ataxia due to cerebellar hypoplasia, cerebral calcifications, extensor hypertonia, progressive psychomotor retardation, and bilateral exudative retinopathy in addition to early onset DC (Revesz et al. 1992. PubMed ID: 1404302).

Because the clinical spectrum of DC is broad and the manifesting symptoms appear at different ages, medical management is specific to each patient, and may involve comprehensive care that needs coordination among different specialties. Screening for leukemia and solid tumors, evaluation by a hematologist for BMF, pulmonary function test, dermatologic examination of skin and nails, and early-onset neurologic findings are some of the suggested monitoring studies (Savage et al. 2009. PubMed ID: 19415736). Genetic testing may aide in establishing a differential diagnosis, predicting the course of disease, and may assist reproductive planning.

DC is characterized by three genetic modes of inheritance: X-linked recessive (DKC1), autosomal dominant (TERC and TINF2), autosomal dominant or autosomal recessive (ACD, RTEL1, and TERT), and autosomal recessive (CTC1, DKC1, NHP2, NOP10, PARN, USB1, and WRAP5). Female carriers of X-linked DKC1 pathogenic variants have been shown to manifest some DC symptoms possibly related to their skewed X-inactivation status (Alder et al. 2013. PubMed ID: 23946118).

Dyskeratosis congenita is caused primarily by defects in telomere maintenance (Walne et al. 2007. PubMed ID: 17507419; Trahan et al. 2010. PubMed ID: 20008900). All DC patients have markedly shorter telomeres compared to age matched healthy individuals (Alter et al. 2007. PubMed ID: 17468339). Telomeres are nucleoprotein complexes located at the ends of linear chromosomes consisting of 6 bp duplex sequence (TTAGGG) found in tandem repeats along with protein complexes. Telomeres protect the chromosome termini from DNA damage. At birth, the size of telomeric repeats range from 8-14 kb, and decreases 50-200 bp with each cell division. Products of 12 genes (see below) participate in telomere biology and integrity, pathogenic variants in which lead to telomere biology disorders (TBDs) that includes a spectrum of disorders with multisystem involvement to single isolated presentations (Bertuch. 2016. PubMed ID: 26400640).

The vast majority of the documented pathogenic variants in these 12 genes are due to missense changes in four genes; TERT, TERC, DKC1, and RTEL1 (HGMD). Copy number changes due to gross deletions and duplications have been documented in only CTC1 and DKC1. Individuals with autosomal dominant DC may have an affected parent, while others may have a de novo variant. Most of the TINF2 variants and some of the DKC1 and TERC variants have been documented de novo (Savage et al. 2016. PubMed ID: 20301779).

While the clinical variability of DC patients is wide, even among members of the same family, the exact penetrance is unknown. Nevertheless, carriers of pathogenic variants in these genes shown full penetrance for the abnormally short telomeres, even among individuals without manifesting symptoms. Consequently, a clinical diagnosis of DC may be established by using the multicolor flow-cytometric method of leukocyte telomere length. This test is performed using fluorescence in situ hybridization (FISH) on a subset of white blood cells from patients with DC and compared against a collection of age-matched healthy individuals to return percentiles of normal telomere lengths. Telomere lengths below the first percentile for age have a 85% positive predictive value among individuals with clinical suspicion of DC, and more than 90% sensitivity and specificity when measured in six leukocyte subsets (Alter et al. 2007. PubMed ID: 17468339).

Among individuals with DC without bone marrow failure, tissue specific mosaicism caused by revertant somatic mosaicism has been documented in TERC. Hence, genetic testing of an alternative tissue, such as a skin biopsy, may be considered when molecular testing of the peripheral blood cells do not yield any discernable pathogenic variant, or when blood cells are found to contain a pathogenic variant with very low levels of mutant allele (Jongmans et al. 2012. PubMed ID: 22341970).

More recently, biallelic pathogenic variants in USB1 have been documented in individuals with DC and an overlapping condition poikiloderma with neutropenia (PN). These individuals had many of the phenotypic features of DC, but without the characteristic short telomeres. The authors of this study propose a new syndrome defined as “USB1 deficiency syndrome” characterized by many of the DC-like features such as bone marrow failure, abnormal skin pigmentation (poikiloderma), nail dystrophy, growth restriction, and cancer predisposition, along with non-DC like features of normal telomere length (Walne et al. 2010. PubMed ID: 20817924; Walne et al. 2016. PubMed ID: 27612988). Due the significant phenotypic overlap, we have included this autosomal recessive gene within this panel.

See individual gene summaries for information on molecular biology of gene products and spectra of pathogenic variants.

Approximately 70% of individuals with dyskeratosis congenita (DC) have pathogenic variants in at least 1 of the 11 known DC genes (Savage et al. 2016. PubMed ID: 20301779). Deleterious variants in DKC1, TINF2, TERC, RTEL1, TERT, and CTC1 account for 20%-25%, 12%-20%, 5%-10%, 2%-8%, 1%-7%, and 1%-3% of pathogenic variants in DC cases, respectively; and pathogenic variants in ACD, NHP2, NOP10, PARN, USB1, and WRAP53 account for ~1-3% of DC cases. Approximately 20-30% of patients with clinical findings of DC do not have any molecular findings in these eleven genes (Savage et al. 2016. PubMed ID: 20301779).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).