Dyskeratosis congenita and the telomere biology disorders

Abstract

Dyskeratosis congenita (DC) is a genetic syndrome with an increasingly appreciated myriad of disease manifestations including life-threatening bone marrow failure (BMF), pulmonary fibrosis, hepatic cirrhosis, and cancer predisposition. Driven by defects in telomere length maintenance, DC is one of a spectrum of telomere biology disorders (TBDs), which includes familial pulmonary fibrosis and the severe variants, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. To date, genes implicated in the TBDs encode telomerase core components (TERT and TERC), factors required for telomerase biogenesis (DKC1, NHP2, NOP2, NAF1, and PARN), telomerase trafficking (WRAP53), telomerase recruitment (ACD), telomere replication and end structure (RTEL1, CTC1, STN1, and POT1), and multiple aspects of telomere biology (TINF2). In this chapter, the principles of telomere length maintenance are described, and a current appraisal of the diagnosis, disease manifestations, treatment options, and molecular genetics of DC and related TBDs is provided.