A novel cause of DKC1‐related bone marrow failure: Partial deletion of the 3′ untranslated region
Jonathan W. Arthur,
Hilda A. Pickett,
Pasquale M. Barbaro,
Tatjana Kilo,
Raja S. Vasireddy,
Traude H. Beilharz,
David R. Powell,
Emma L. Hackett,
Bruce Bennetts,
Julie A. Curtin,
Kristi Jones,
John Christodoulou,
Roger R. Reddel,
Juliana Teo,
Tracy M. Bryan
Affiliations
Jonathan W. Arthur
Children's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales Australia
Hilda A. Pickett
Children's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales Australia
Pasquale M. Barbaro
Children's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales Australia
Tatjana Kilo
Haematology Department Children's Hospital at Westmead Westmead New South Wales Australia
Raja S. Vasireddy
Haematology Department Children's Hospital at Westmead Westmead New South Wales Australia
Traude H. Beilharz
Monash Biomedicine Discovery Institute Department of Biochemistry and Molecular Biology, Monash University Clayton Victoria Australia
David R. Powell
Monash Bioinformatics Platform Monash University Clayton Victoria Australia
Emma L. Hackett
Department of Molecular Genetics Children's Hospital Westmead Westmead New South Wales Australia
Bruce Bennetts
Department of Molecular Genetics Children's Hospital Westmead Westmead New South Wales Australia
Julie A. Curtin
Haematology Department Children's Hospital at Westmead Westmead New South Wales Australia
Kristi Jones
Disciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and Health University of Sydney Westmead New South Wales Australia
John Christodoulou
Disciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and Health University of Sydney Westmead New South Wales Australia
Roger R. Reddel
Children's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales Australia
Juliana Teo
Haematology Department Children's Hospital at Westmead Westmead New South Wales Australia
Tracy M. Bryan
Children's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales Australia
Abstract Telomere biology disorders (TBDs), including dyskeratosis congenita (DC), are a group of rare inherited diseases characterized by very short telomeres. Mutations in the components of the enzyme telomerase can lead to insufficient telomere maintenance in hematopoietic stem cells, resulting in the bone marrow failure that is characteristic of these disorders. While an increasing number of genes are being linked to TBDs, the causative mutation remains unidentified in 30‐40% of patients with DC. There is therefore a need for whole genome sequencing (WGS) in these families to identify novel genes, or mutations in regulatory regions of known disease‐causing genes. Here we describe a family in which a partial deletion of the 3′ untranslated region (3′ UTR) of DKC1, encoding the protein dyskerin, was identified by WGS, despite being missed by whole exome sequencing. The deletion segregated with disease across the family and resulted in reduced levels of DKC1 mRNA in the proband. We demonstrate that the DKC1 3′ UTR contains two polyadenylation signals, both of which were removed by this deletion, likely causing mRNA instability. Consistent with the major function of dyskerin in stabilization of the RNA subunit of telomerase, hTR, the level of hTR was also reduced in the proband, providing a molecular basis for his very short telomeres. This study demonstrates that the terminal region of the 3′ UTR of the DKC1 gene is essential for gene function and illustrates the importance of analyzing regulatory regions of the genome for molecular diagnosis of inherited disease.
