Genetics of Dyskeratosis Congenita

Dyskeratosis congenita (DC) is a rare, inherited, skin and bone marrow failure disease. It is a multisystem disorder which is heterogeneous at the genetic and clinical levels. Genetically, nine genes have so far been identified whose mutation causes DC, and inheritance of the disease can be X linked, autosomal dominant or recessive. Clinically, the disease can present in childhood as classical DC with a characteristic triad of nail dystrophy, leukoplakia and abnormal skin pigmentation along with progressive bone marrow failure. More severe forms presenting in infancy and milder forms in adults, as aplastic anaemia or pulmonary fibrosis, exist. All forms of the disease with known pathogenesis are due to failure of telomere maintenance, often leading to stem cell exhaustion. Recent progress in the identification of mutations in human syndromes has revealed that DC overlaps clinically and genetically with a number of other rare syndromes. Key Concepts: The major cause of death in DC is bone marrow failure. The most common form of DC is X linked. In the X-linked form, females are not, or very mildly, affected, but they show extremely skewed X-inactivation, with cells expressing the mutated gene being outgrown by cells expressing the wild type gene. Dyskeratosis congenita is a disease caused by defective telomere maintenance. Nine genes have been discovered to cause dyskeratosis congenita when mutated, and their products are involved in telomerase and its assembly or as part of the telomere. When the disease is caused by mutations in the core components of telomerase, TERT and TERC families show an increase in severity of the disease in later generations, a phenomenon known as genetic anticipation. Genetic anticipation is due to shortening of telomeres from one generation to the next. Some DC mutations are also known causes of pulmonary fibrosis, liver fibrosis and Coats retinopathy. Now that genes responsible for rare syndromes are being discovered, it is becoming evident that there is overlap between DC and several other rare syndromes that have been described. Keywords: telomerase; telomere; dyskerin; TERC; TIN2; Hoyeraal Hreidarsson; anticipation; pulmonary fibrosis; aplastic anaemia; telomere length