Dyskeratosis Congenita (DC) and Related Telomere Biology Disorders Panel

Dyskeratosis congenita (DC) is a rare inherited disorder associated with impaired telomere maintenance resulting in short telomeres. The phenotypic spectrum is broad and includes individuals affected with classic DC involving multiorgan symptoms, as well as individuals with very short telomeres and isolated clinical findings. Classic DC is primarily characterized by a triad of cardinal phenotypic features including 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. 2023. PubMed ID: 20301779). 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 eyelash growth, prematurely grey hair, alopecia, dental abnormalities, short stature, microcephaly, developmental delay, hypogonadism, liver cirrhosis, osteoporosis, gastrointestinal telangiectasias, and pulmonary arteriovenous malformations (Savage et al. 2023. PubMed ID: 20301779; Savage. 2022. PubMed ID: 36485133). A diagnosis of DC in an individual with characteristic clinical findings can be established by determining the lymphocyte telomere length and/or identifying pathogenic variants in genes associated with dyskeratosis congenita/telomere biology disorder(s) (Savage et al. 2023. PubMed ID: 20301779).

Although DC is a rare condition, the exact prevalence is unknown. Age of onset and progression of DC varies considerably among individuals, even among individuals within the same family. Three more severe forms of DC/telomere biology disorders (TBD) have been identified to date: Hoyeraal-Hreidarsson syndrome (HHS), Revesz syndrome (RS), and Coats plus syndrome (Savage et al. 2023. PubMed ID: 20301779). Individuals with HHS present with classical features of DC/TBD in early in childhood. Additional clinical findings include cerebellar hypoplasia, developmental delay, immunodeficiency, and bone marrow failure (Hoyeraal et al. 1970. PubMed ID: 5442429; Hreidarsson et al. 1988. PubMed ID: 3201986). Individuals with RS also present in early childhood with classical features of DC/TBD and bilateral exudative retinopathy. In addition, these individuals may have intracranial calcifications and bone marrow failure (Revesz et al. 1992. PubMed ID: 1404302; Savage et al. 2023. PubMed ID: 20301779). Individuals with cerebroretinal microangiopathy with calcifications and cysts, also known as "Coats plus" syndrome, may present with dystrophic nails, sparse or graying hair, bilateral exudative retinopathy, retinal telangiectasias, intracranial calcifications, osteopenia with tendency to fracture with poor bone healing, and gastrointestinal vascular ectasias (Linnankivi et al. 2006. PubMed ID: 16943371, Briggs et al. 2008. PubMed ID: 18076099; Anderson et al. 2012. PubMed ID: 22267198, Polvi et al. 2012. PubMed ID: 22387016). The clinical spectrum of DC is broad, and the manifesting symptoms appear at different ages. Therefore the medical management is specific to each patient and may involve comprehensive care that needs coordination among different specialties. Genetic testing may assist in establishing a diagnosis and predicting the course of disease.

The mode of inheritance of dyskeratosis congenita and the related telomere biology disorders (DC/TBD) depends on the gene involved. DC is characterized by three genetic modes of inheritance: X-linked recessive (DKC1), autosomal dominant (NAF1, RPA1, TERC, TINF2, and ZCCHC8), autosomal dominant or autosomal recessive (ACD, PARN, RTEL1 and TERT), and autosomal recessive (CTC1, NHP2, NOP10, POT1, STN1, USB1 and WRAP53). 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). Individuals with autosomal dominant DC may inherit the pathogenic variant from an affected parent, while others may have the disorder because of a de novo variant. Most of the TINF2 variants have been documented de novo, while the proportion of affected individuals by de novo variants in other genes is currently unknown (Savage et al. 2023. PubMed ID: 20301779). In rare cases, the proband may inherit a pathogenic variant from a parent with germline mosaicism. Individuals with heterozygous pathogenic variants in genes associated with both AD and AR modes of inheritance may be at elevated risk for DC/TBD-related complications (Savage et al. 2023. PubMed ID: 20301779). 

In addition, tissue-restricted mosaicism has been reported in a limited number of individuals with DC/TBD (Jongmans et al. 2012. PubMed ID: 22341970; Sharma et al. 2022. PubMed ID: 34767620). Hence, genetic testing of an alternative tissue, such as skin biopsy, may be considered for individuals who meet the diagnostic criteria for DC/TBD, but do not have a pathogenic variant identified on molecular genetic testing. 

Pathogenic variants in USB1 have also been documented in individuals with autosomal recessive poikiloderma with neutropenia (PN). These individuals have many overlapping clinical features with DC (dystrophic nails, abnormal skin pigmentation and increased risk for myelodysplastic syndrome), but without the characteristic short telomeres (Walne et al. 2010. PubMed ID: 20817924; Walne et al. 2016. PubMed ID: 27612988; Colombo et al. 2018. PubMed ID: 29770900). Due to the significant phenotypic overlap, we have included this autosomal recessive gene in this panel.

Approximately 80% of individuals with dyskeratosis congenita (DC) have pathogenic variants in at least one of the 16 known DC genes (Savage et al. 2023. PubMed ID: 20301779). Pathogenic variants in DKC1, TINF2, TERC, RTEL1, TERT, and CTC1 genes account for 20%-25%, 12%-20%, 5%-10%, 2%-8%, 1%-7%, and 1%-3% of pathogenic variants in DC cases, respectively. Approximately 20% of patients with clinical findings of DC do not have a molecular finding (Savage et al. 2023. PubMed ID: 20301779).

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

This panel provides approximately 99.9% 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).