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Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing.
Nat Commun 2015; 6:8718NC

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.

Authors+Show Affiliations

The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8. The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1Z5. Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada M5G 1X8.Donnelly Centre, University of Toronto, Toronto, Ontario, Canada M5S 3E1.The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.Division for Immunology and Allergy, Canadian Center for Primary Immunodeficiency, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.Division for Immunology and Allergy, Canadian Center for Primary Immunodeficiency, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, New South Wales 2031, Australia.Department of Allergy and Immunology, The Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia.Queensland Paediatric Immunology and Allergy Service, The Lady Cilento Children's Hospital, South Brisbane, Queensland 4101, Australia. School of Medicine, University of Queensland, Brisbane, Queensland 4006, Australia.Queensland Paediatric Immunology and Allergy Service, The Lady Cilento Children's Hospital, South Brisbane, Queensland 4101, Australia. School of Medicine, University of Queensland, Brisbane, Queensland 4006, Australia.Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.Donnelly Centre, University of Toronto, Toronto, Ontario, Canada M5S 3E1. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada M5G 1X8. Division for Immunology and Allergy, Canadian Center for Primary Immunodeficiency, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8. McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada M5G 0A4. Centre of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26522830

Citation

Merico, Daniele, et al. "Compound Heterozygous Mutations in the Noncoding RNU4ATAC Cause Roifman Syndrome By Disrupting Minor Intron Splicing." Nature Communications, vol. 6, 2015, p. 8718.
Merico D, Roifman M, Braunschweig U, et al. Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. Nat Commun. 2015;6:8718.
Merico, D., Roifman, M., Braunschweig, U., Yuen, R. K., Alexandrova, R., Bates, A., ... Scherer, S. W. (2015). Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. Nature Communications, 6, p. 8718. doi:10.1038/ncomms9718.
Merico D, et al. Compound Heterozygous Mutations in the Noncoding RNU4ATAC Cause Roifman Syndrome By Disrupting Minor Intron Splicing. Nat Commun. 2015 Nov 2;6:8718. PubMed PMID: 26522830.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. AU - Merico,Daniele, AU - Roifman,Maian, AU - Braunschweig,Ulrich, AU - Yuen,Ryan K C, AU - Alexandrova,Roumiana, AU - Bates,Andrea, AU - Reid,Brenda, AU - Nalpathamkalam,Thomas, AU - Wang,Zhuozhi, AU - Thiruvahindrapuram,Bhooma, AU - Gray,Paul, AU - Kakakios,Alyson, AU - Peake,Jane, AU - Hogarth,Stephanie, AU - Manson,David, AU - Buncic,Raymond, AU - Pereira,Sergio L, AU - Herbrick,Jo-Anne, AU - Blencowe,Benjamin J, AU - Roifman,Chaim M, AU - Scherer,Stephen W, Y1 - 2015/11/02/ PY - 2015/02/02/received PY - 2015/09/25/accepted PY - 2015/11/3/entrez PY - 2015/11/3/pubmed PY - 2016/5/18/medline SP - 8718 EP - 8718 JF - Nature communications JO - Nat Commun VL - 6 N2 - 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/26522830/Compound_heterozygous_mutations_in_the_noncoding_RNU4ATAC_cause_Roifman_Syndrome_by_disrupting_minor_intron_splicing_ L2 - http://dx.doi.org/10.1038/ncomms9718 DB - PRIME DP - Unbound Medicine ER -