title: Constitutional mutations in RTEL1 cause severe dyskeratosis congenita.
abstract: 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.
authors: Centre for Paediatrics, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, London, UK. a.walne@qmul.ac.uk
authors: Amanda J
authors: AJ
authors: Walne
authors: Tom
authors: T
authors: Vulliamy
authors: Michael
authors: M
authors: Kirwan
authors: Vincent
authors: V
authors: Plagnol
authors: Inderjeet
authors: I
authors: Dokal
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics*; D019871:Dyskeratosis Congenita / Q000235:genetics*; D059472:Exome; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods; D020539:Sequence Analysis, Protein / Q000379:methods; D016615:Telomere / Q000235:genetics; D059506:Telomere Shortening / Q000235:genetics
chemical_list: C532890:RTEL1 protein, human; D004265:DNA Helicases