title: Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing.
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.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: 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.
authors.forename: Maian
authors.initials: M
authors.lastname: Roifman
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Ulrich
authors.identifier: http://orcid.org/0000-0001-6653-0926
authors.initials: U
authors.lastname: Braunschweig
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Ryan K C
authors.initials: RK
authors.lastname: Yuen
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Roumiana
authors.initials: R
authors.lastname: Alexandrova
authors.affiliation: Division for Immunology and Allergy, Canadian Center for Primary Immunodeficiency, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bates
authors.affiliation: Division for Immunology and Allergy, Canadian Center for Primary Immunodeficiency, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Brenda
authors.initials: B
authors.lastname: Reid
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nalpathamkalam
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Zhuozhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Bhooma
authors.initials: B
authors.lastname: Thiruvahindrapuram
authors.affiliation: Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, New South Wales 2031, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gray
authors.affiliation: Department of Allergy and Immunology, The Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia.
authors.forename: Alyson
authors.initials: A
authors.lastname: Kakakios
authors.affiliation: 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.
authors.forename: Jane
authors.initials: J
authors.lastname: Peake
authors.affiliation: 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.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hogarth
authors.affiliation: Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: David
authors.initials: D
authors.lastname: Manson
authors.affiliation: Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Raymond
authors.initials: R
authors.lastname: Buncic
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Sergio L
authors.initials: SL
authors.lastname: Pereira
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Herbrick
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario, Canada M5S 3E1.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.affiliation: 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.
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.affiliation: 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.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000483:Alleles; D001483:Base Sequence; D009202:Cardiomyopathies / Q000235:genetics*; D002675:Child, Preschool; D004392:Dwarfism / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007438:Introns; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D000081207:Primary Immunodeficiency Diseases; D012326:RNA Splicing; D012342:RNA, Small Nuclear / Q000737:chemistry / Q000235:genetics*; D012164:Retinal Diseases / Q000235:genetics*; D020506:Untranslated Regions
chemical_list: D012342:RNA, Small Nuclear; C000590616:RNU4ATAC RNA, human; D020506:Untranslated Regions