title: Differences in disease severity but similar telomere lengths in genetic subgroups of patients with telomerase and shelterin mutations.
abstract: The bone marrow failure syndrome dyskeratosis congenita (DC) has been considered to be a disorder of telomere maintenance in which disease features arise due to accelerated shortening of telomeres. By screening core components of the telomerase and shelterin complexes in patients with DC and related bone marrow failure syndromes we have identified 24 novel mutations: 11 in the RNA component of telomerase (TERC), 8 in the reverse transcriptase component (TERT), 4 in dyskerin (DKC1) and 1 in TRF1-interacting nuclear factor 2 (TINF2). This has prompted us to review these genetic subtypes in terms of telomere length, telomerase activity and clinical presentation among 194 genetically characterised index cases recruited onto the registry in London. While those with DKC1 and TINF2 mutations present at a younger age and have more disease features than those with TERC or TERT mutations, there is no difference in telomere length between these groups. There is no difference in the age of onset and numbers of disease features seen in those with TERC and TERT mutations despite the fact that the latter show higher levels of telomerase activity in vitro. The incidence of aplastic anaemia is greater in patients with TERC or TINF2 mutations compared to patients with DKC1 mutations, and cancer incidence is highest in patients with TERC mutations. These data are the first to provide robust comparisons between different genetic subtypes of telomerase and shelterin mutations (the "telomereopathies") and clearly demonstrate that disease severity is not explained by telomere length alone.
authors.affiliation: Centre for Paediatrics, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. t.vulliamy@qmul.ac.uk
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Vulliamy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kirwan
authors.forename: Richard
authors.initials: R
authors.lastname: Beswick
authors.forename: Upal
authors.initials: U
authors.lastname: Hossain
authors.forename: Charlotte
authors.initials: C
authors.lastname: Baqai
authors.forename: Anna
authors.initials: A
authors.lastname: Ratcliffe
authors.forename: Judith
authors.initials: J
authors.lastname: Marsh
authors.forename: Amanda
authors.initials: A
authors.lastname: Walne
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012720:Severity of Illness Index; D000089804:Shelterin Complex; D019098:Telomerase / Q000235:genetics*; D059505:Telomere Homeostasis; D034501:Telomere-Binding Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; C509186:TERT protein, human; D019098:Telomerase