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

Nat Commun. 2015 Nov 2;6:8718. doi: 10.1038/ncomms9718.

Daniele Merico ¹, Maian Roifman ² ³ ⁴, Ulrich Braunschweig ⁵, Ryan K C Yuen ¹, Roumiana Alexandrova ¹, Andrea Bates ⁶, Brenda Reid ⁶, Thomas Nalpathamkalam ¹, Zhuozhi Wang ¹, Bhooma Thiruvahindrapuram ¹, Paul Gray ⁷, Alyson Kakakios ⁸, Jane Peake ⁹ ¹⁰, Stephanie Hogarth ⁹ ¹⁰, David Manson ¹¹, Raymond Buncic ¹², Sergio L Pereira ¹, Jo-Anne Herbrick ¹, Benjamin J Blencowe ⁵ ¹³, Chaim M Roifman ⁴ ⁶, Stephen W Scherer ¹ ¹³ ¹⁴ ¹⁵

Affiliations

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

PMID: 26522830 DOI: 10.1038/ncomms9718

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.

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