Dyskeratosis Congenita (DC) via the RTEL1 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 (Dvorak et al. 2015. PubMed ID: 25455995). 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. 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. 2016. PubMed ID: 20301779).

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 and TERT (Savage et al. 20016. PubMed ID: 20301779).

RTEL1 encodes a DNA helicase that functions in the stability, elongation and protection of telomeres (Uringa et al. 2012. PubMed ID: 22593209). It has been shown that RTEL1 pathogenic variants can account for both autosomal dominant and autosomal recessive dyskeratosis congenita (Ballew et al. 2013. PubMed ID: 23329068). One study showed that 7 out of 23 cases with RTEL1 variants segregated in an autosomal recessive manner (Walne et al. 2013. PubMed ID: 23453664). Another study examined 3 families and 2 out of 3 showed an autosomal dominant pattern of inheritance, with the third exhibiting a compound heterozygous state (Ballew et al. 2013. PubMed ID: 23329068). It is difficult to determine which mode of inheritance for DC is more commonly associated with RTEL1 pathogenic variants. Individuals with autosomal dominant heterozygous pathogenic variants in RTEL1 may develop clinical features of DC at later ages (Savage et al. 2016. PubMed ID: 20301779). Biallelic pathogenic variants in RTEL1 have been identified in individuals with the severe DC subtype, Hoyeraal Hreidarsson syndrome (Ballew et al. 2013. PubMed ID: 23329068; Walne et al. 2013. PubMed ID: 23453664).

Pathogenic variants, mostly missense, in RTEL1 have also been reported in cases of pulmonary fibrosis (Petrovski et al. 2017. PubMed ID: 28099038).

To date, pathogenic variants reported in the RTEL1 gene include missense, splicing, nonsense and frameshift deletions (Human Gene Mutation Database). A founder variant in RTEL1, known most commonly as c.3791G>A; p.Arg1264His (a.k.a c.3724+139G>A, NM_032957.4) with a carrier frequency of 0.4%-1% has been identified in individuals of Ashkenazi Jewish ancestry (Fedick et al. 2014. PubMed ID: 25047097).

Approximately 70% of individuals with dyskeratosis congenita (DC) have pathogenic variants in at least 1 of the 11 known DC genes. Pathogenic variants in RTEL1 account for 2-8% of DC cases (Savage et al. 20016. PubMed ID: 20301779).

This test provides full coverage of all coding exons of the RTEL1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.