Journal Article

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

Buncic, Raymond, Wang, Zhuozhi, Blencowe, Benjamin J., Merico, Daniele, Braunschweig, Ulrich, Peake, Jane, Gray, Paul, Thiruvahindrapuram, Bhooma, Kakakios, Alyson, Manson, David, Roifman, Maian, Yuen, Ryan K. C., Hogarth, Stephanie, Herbrick, Jo-Anne, Nalpathamkalam, Thomas, Roifman, Chaim M., Reid, Brenda, Scherer, Stephen W., Pereira, Sergio L., Alexandrova, Roumiana, Bates, Andrea

2015

Overview

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. Roifman Syndrome is a rare disorder whose disease manifestations include growth retardation, spondyloepiphyseal dysplasia and immunodeficiency. Here, the authors use whole-genome sequencing to discover that rare compound heterozygous variants disrupting the small nuclear RNA gene RNU4ATAC cause Roifman Syndrome.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 38/91 / 631/208/2489/144 / 631/208/514 / 631/337/1645/1792 / 692/699 / Alleles / Base Sequence / Cardiomyopathies - genetics / Child, Preschool / Dwarfism - genetics / Female / Fetal Growth Retardation - genetics / Humanities and Social Sciences / Humans / Immunologic Deficiency Syndromes - genetics / Introns / Male / Mental Retardation, X-Linked - genetics / Microcephaly - genetics / Molecular Sequence Data / multidisciplinary / Nucleic Acid Conformation / Osteochondrodysplasias - genetics / Pedigree / Point Mutation / Retinal Diseases - genetics / RNA Splicing / RNA, Small Nuclear - chemistry / RNA, Small Nuclear - genetics / Science / Science (multidisciplinary) / Untranslated Regions