title: Triallelic and epigenetic-like inheritance in human disorders of telomerase.
abstract: Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution.
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;
authors.forename: Laura C
authors.initials: LC
authors.lastname: Collopy
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Walne
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;
authors.forename: Shirleny
authors.initials: S
authors.lastname: Cardoso
authors.affiliation: Department of Paediatric Haematology, Imperial College Healthcare National Health Service Trust, St. Mary's Hospital, London, United Kingdom;
authors.forename: Josu
authors.initials: J
authors.lastname: de la Fuente
authors.affiliation: Paediatric Haematology-Oncology Unit, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia;
authors.forename: Mahfuzah
authors.initials: M
authors.lastname: Mohamed
authors.affiliation: Department of Genetics, Spectrum Health, Grand Rapids, MI;
authors.forename: Helga
authors.initials: H
authors.lastname: Toriello
authors.affiliation: Paediatric Haematology Unit, Schneider Children's Hospital, Medical Center of Israel, Petach Tikvah, Israel; and.
authors.forename: Hannah
authors.initials: H
authors.lastname: Tamary
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;
authors.forename: Adam J Y V
authors.initials: AJ
authors.lastname: Ling
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;
authors.forename: Timothy
authors.initials: T
authors.lastname: Lloyd
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kassam
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;
authors.forename: Hemanth
authors.initials: H
authors.lastname: Tummala
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Vulliamy
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Barts Health, London, United Kingdom.
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002478:Cells, Cultured; D015331:Cohort Studies; D019871:Dyskeratosis Congenita / Q000235:genetics*; D044127:Epigenesis, Genetic; D005190:Family; D006801:Humans; D040582:Inheritance Patterns; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012313:RNA / Q000235:genetics; D019098:Telomerase / Q000235:genetics*
chemical_list: C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase