title: Telomere length measurement can distinguish pathogenic from non-pathogenic variants in the shelterin component, TIN2.
abstract: Dyskeratosis congenita (DC) is a heterogeneous bone marrow failure syndrome with seven disease-causing genes identified to date, six of which are linked to telomere maintenance. Mutations in one of these genes (TINF2), which encodes a component of the shelterin complex, are associated with particularly short telomeres. Among the 224 consecutive patients with different forms of bone marrow failure (46 with DC, 122 with aplastic anaemia and 57 with some features of DC), we have identified 16 new families with variants in exon 6 of the TINF2 gene, eight of which are novel. We observe that the phenotype associated with these mutations extends to a severe early presentation, not always classified as DC. In addition, we see that some of the variants identified are not associated with short telomeres and are also found in asymptomatic individuals. In the absence of any direct functional assay, the data indicates that the telomere length measurement can inform us as to which variants in TINF2 are pathogenic and which may be non-pathogenic.
authors.affiliation: Centre for Paediatrics, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. t.vulliamy@qmul.ac.uk
authors.forename: T
authors.initials: T
authors.lastname: Vulliamy
authors.forename: R
authors.initials: R
authors.lastname: Beswick
authors.forename: M J
authors.initials: MJ
authors.lastname: Kirwan
authors.forename: U
authors.initials: U
authors.lastname: Hossain
authors.forename: A J
authors.initials: AJ
authors.lastname: Walne
authors.forename: I
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D019871:Dyskeratosis Congenita / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005317:Fetal Growth Retardation / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D016368:Frameshift Mutation; D015894:Genome, Human; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D016415:Sequence Alignment; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins