Dyskeratosis Congenita (DC) and Revesz Syndrome via the TINF2 Gene

Dyskeratosis congenita (DC) is a disease characterized by multiple anomalies including abnormal skin pigmentation, nail dystrophy, mucosal leukoplakia, bone marrow failure and an increase in cancer predisposition (Walne et al. 2007. PubMed ID: 17507419; Kirwan et al. 2008. PubMed ID: 18005359). Individuals affected with DC can exhibit other features including liver cirrhosis, osteoporosis, pulmonary fibrosis and learning difficulties. 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. Those who have minimal physical 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. 2009. PubMed ID: 20301779). Variants in the TINF2 gene also cause Revesz syndrome, a severe type of DC that is characterized by bilateral exudative retinopathy or Coats disease and bone marrow failure (Bertuch et al. 2015. PubMed ID: 26400640).

Dyskeratosis congenita is caused primarily by defects in telomere maintenance (Walne et al. 2007. PubMed ID: 17507419; Trahan et al. 2010. PubMed ID: 20008900). DC is characterized by three genetic subtypes: X-linked recessive, caused by variants in the DKC1 gene, autosomal dominant DC caused by heterozygous variants in TERC, TINF2 or TERT genes, and autosomal recessive DC which involves several genes including ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, WRAP53 as well as TERT (Savage et al. 2009. PubMed ID: 20301779).

TINF2-related DC and Revesz syndrome are inherited in an autosomal dominant manner, although the majority of variants are de novo (Bertuch et al. 2015. PubMed ID: 26400640). TINF2 encodes TERF1-interacting nuclear factor 2 (TINF2), a component of the telomere shelterin protein complex, which is needed for telomere maintenance. Approximately 70% of reported pathogenic variants are missense (Savage et al. 2008. PubMed ID: 18252230).

Approximately 70% of individuals with dyskeratosis congenita (DC) have pathogenic variants in at least 1 of the 11 known DC genes. The TINF2 gene accounts for 11-24% of pathogenic variants reported in DC patients (Walne et al. 2008. PubMed ID: 18669893; Armanios et al. 2012. PubMed ID: 22965356).

This test provides full coverage of all coding exons of the TINF2 gene 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 full 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).