Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing

Daniele Merico, Maian Roifman, Ulrich Braunschweig, Ryan K. C. Yuen, Roumiana Alexandrova, Andrea Bates, Brenda Reid, Thomas Nalpathamkalam, Zhuozhi Wang, Bhooma Thiruvahindrapuram, Paul Gray, Alyson Kakakios, Jane Peake, Stephanie Hogarth, David Manson, Raymond Buncic, Sergio L. Pereira, Jo-Anne Herbrick, Benjamin J. Blencowe, Chaim M. Roifman () and Stephen W. Scherer ()
Additional contact information
Daniele Merico: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children
Maian Roifman: The Hospital for Sick Children
Ulrich Braunschweig: Donnelly Centre, University of Toronto
Ryan K. C. Yuen: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children
Roumiana Alexandrova: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children
Andrea Bates: Canadian Center for Primary Immunodeficiency, The Hospital for Sick Children
Brenda Reid: Canadian Center for Primary Immunodeficiency, The Hospital for Sick Children
Thomas Nalpathamkalam: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children
Zhuozhi Wang: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children
Bhooma Thiruvahindrapuram: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children
Paul Gray: Sydney Children’s Hospital
Alyson Kakakios: The Children’s Hospital at Westmead
Jane Peake: Queensland Paediatric Immunology and Allergy Service, The Lady Cilento Children's Hospital
Stephanie Hogarth: Queensland Paediatric Immunology and Allergy Service, The Lady Cilento Children's Hospital
David Manson: The Hospital for Sick Children
Raymond Buncic: The Hospital for Sick Children
Sergio L. Pereira: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children
Jo-Anne Herbrick: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children
Benjamin J. Blencowe: Donnelly Centre, University of Toronto
Chaim M. Roifman: University of Toronto
Stephen W. Scherer: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported.

Date: 2015
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9718

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DOI: 10.1038/ncomms9718

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