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

Merico, Daniele, Roifman, Maian, Braunschweig, Ulrich, Yuen, Ryan K. C., Alexandrova, Roumiana, Bates, Andrea, Reid, Brenda, Nalpathamkalam, Thomas, Wang, Zhuozhi, Thiruvahindrapuram, Bhooma, Gray, Paul, Kakakios, Alyson, Peake, Jane, Hogarth, Stephanie, Manson, David, Buncic, Raymond, Pereira, Sergio L., Herbrick, Jo-Anne, Blencowe, Benjamin J., Roifman, Chaim M. and Scherer, Stephen W. (2015) Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. Nature Communications, 6 1-10. doi:10.1038/ncomms9718

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Author Merico, Daniele
Roifman, Maian
Braunschweig, Ulrich
Yuen, Ryan K. C.
Alexandrova, Roumiana
Bates, Andrea
Reid, Brenda
Nalpathamkalam, Thomas
Wang, Zhuozhi
Thiruvahindrapuram, Bhooma
Gray, Paul
Kakakios, Alyson
Peake, Jane
Hogarth, Stephanie
Manson, David
Buncic, Raymond
Pereira, Sergio L.
Herbrick, Jo-Anne
Blencowe, Benjamin J.
Roifman, Chaim M.
Scherer, Stephen W.
Title Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2015-11-02
Year available 2015
Sub-type Article (original research)
DOI 10.1038/ncomms9718
Open Access Status DOI
Volume 6
Start page 1
End page 10
Total pages 10
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2016
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
 
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