Date Published: March 07, 2013
Author(s): Amanda J. Walne, Tom Vulliamy, Michael Kirwan, Vincent Plagnol, Inderjeet Dokal.
Dyskeratosis congenita (DC) and its phenotypically severe variant, Hoyeraal-Hreidarsson syndrome (HHS), are multisystem bone-marrow-failure syndromes in which the principal pathology is defective telomere maintenance. The genetic basis of many cases of DC and HHS remains unknown. Using whole-exome sequencing, we identified biallelic mutations in RTEL1, encoding a helicase essential for telomere maintenance and regulation of homologous recombination, in an individual with familial HHS. Additional screening of RTEL1 identified biallelic mutations in 6/23 index cases with HHS but none in 102 DC or DC-like cases. All 11 mutations in ten HHS individuals from seven families segregated in an autosomal-recessive manner, and telomere lengths were significantly shorter in cases than in controls (p = 0.0003). This group had significantly higher levels of telomeric circles, produced as a consequence of incorrect processing of telomere ends, than did controls (p = 0.0148). These biallelic RTEL1 mutations are responsible for a major subgroup (∼29%) of HHS. Our studies show that cells harboring these mutations have significant defects in telomere maintenance, but not in homologous recombination, and that incorrect resolution of T-loops is a mechanism for telomere shortening and disease causation in humans. They also demonstrate the severe multisystem consequences of its dysfunction.
Dyskeratosis congenita (DC [MIM 305000]) is a complex bone-marrow (BM)-failure syndrome in which the principal pathology is defective telomere maintenance and is associated with short telomeres.1–3 Eight of the genes known to be mutated in DC are involved in telomere maintenance and account for the genetic basis of approximately 60% of DC cases.3–6 The classical presentation of DC includes abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. Individuals with DC frequently develop BM failure and are at a high risk of developing cancer, as well as a variety of other features.7 Hoyeraal-Hreidarsson syndrome (HHS [MIM 300240]) is a phenotypically severe DC variant that is characterized by a variety of features, including BM failure, intrauterine growth restriction, developmental delay, cerebellar hypoplasia, immunodeficiency,8 and usually short telomeres. Although the genetic basis of some cases of HHS has been elucidated, in many cases it remains unknown.