Fulltext

RNU4ATAC-opathy: Clinical, molecular, and transcriptomic insights from a large cohort

Matalon DR 1 , Duker AL 2 , Arriaga TM 3 , Russell K 4 , Mendez HR 5 , Bonner DE 6 Show all authors , Harley ME 7 , Singer-Berk M 4 , Wojcik MH 8 , Pais L 4 , DiTroia S 4 , O'Leary M 4 , Cassini T 9 , Ezell K 9 , Niehaus AD 6 , Kaplan J 10 , Wargowski DS 11 , Smid CJ 11 , Longenecker ED 2 , Rodriguez Barreto AM 12 , Miller DE 13 , Keefe AC 14 , Calderwood L 6 , Enns GM 6 , Tekin M 15 , Bivona SA 15 , Vora NL 16 , Gilmore KL 16 , Khan TN 17 , Davis EE 18 , Wang AW 19 , Khan S 20 , Maddirevula S 21 , Al Abdi L 20 , Abuyousef O 20 , Shamseldin HE 20 , Alkhalifi S 22 , Abdulwahab F 20 , Alqahtani M 20 , Alhumaidi ZA 22 , Nadeef S 20 , Al Hashem AM 20 , Bakur K 23 , Faqeih EA 24 , Abdalla E 25 , Clarke A 26 , Fletcher E 27 , Keng WT 28 , Ousager LB 29 , de Silva DC 30 , Haniffa M 28 , Mari F 31 , Lam W 32 , Campbell J 33 , Homfray T 34 , Nampoothiri S 35 , Li C 36 , Chaudhari BP 37 , Truxal K 37 , Genomics Research to Elucidate the Genetics of Rare Diseases consortium, Undiagnosed Diseases Network , Bernstein JA 38 , Montgomery SB 39 , Wheeler MT 40 , Alkuraya FS 41 , O'Donnell-Luria A 8 , Jackson AP 7 , Campbell IM 42 , Ganesh VS 43 , Robertson N 44 , Lemire G 45

Affiliations 

  • 1 Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA. Electronic address: matalon@stanford.edu
  • 2 Division of Orthogenetics, Department of Pediatrics, Nemours Children's Hospital, Wilmington, DE
  • 3 Department of Genetics, Stanford University, Stanford, CA
  • 4 Broad Institute Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
  • 5 Department of Medicine, Stanford University, Standford, CA
  • 6 Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA
  • 7 Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
  • 8 Broad Institute Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA
  • 9 Vanderbilt University Medical Center, Nashville, TN
  • 10 Cleveland Clinic Foundation, Cleveland, OH
  • 11 Division of Genetics and Metabolism, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI
  • 12 Division of clinical genetics, Nicklaus Children's Hospital, Miami, FL
  • 13 Division of Genetic Medicine, Department of Pediatrics; Department of Laboratory Medicine and Pathology; Brotman Baty Institute for Precision Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA
  • 14 Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA
  • 15 John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL
  • 16 Obstetrics and Gynecology; Division of Maternal Fetal Medicine, UNC Chapel Hill School of Medicine, Chapel Hill, NC
  • 17 Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
  • 18 Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Department of Pediatrics and Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL
  • 19 ORIC Pharmaceuticals, South San Francisco, CA
  • 20 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  • 21 Precision Medicine Laboratory Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  • 22 Newborn Screening program, Ministry of Health, Eastern Province, Saudi Arabia
  • 23 Lifera Omics, Riyadh, Saudi Arabia
  • 24 Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
  • 25 Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria Egypt
  • 26 Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom
  • 27 Department of Clinical Genetics, Centre for Genomic and Experimental Medicine, Western General Hospital, Crewe Road South, Edinburgh, United Kingdom
  • 28 Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
  • 29 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
  • 30 Department of Physiology, Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka
  • 31 Department of Medicine, Surgery and Neurosciences, University of Siena, Italy and Clinical Pathology Unit, University Hospital of Siena, Siena, Italy
  • 32 South East of Scotland Clinical Genetics Service, Edinburgh, United Kingdom
  • 33 Clinical Genomics Service, Leeds Teaching Hospitals National Health Service Trust, Leeds, United Kingdom
  • 34 Medical Genetics Service, St George's University Hospital and Royal Brompton Hospital London, London, United Kingdom
  • 35 Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Kochi, India
  • 36 Department of Paediatrics, McMaster University Medical Center, Hamilton, ON, Canada
  • 37 Division of Genetics and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH; Department of Pediatrics, The Ohio State University, Columbus, OH, USA
  • 38 Department of Pediatrics, Stanford University School of Medicine, Stanford University, Stanford, CA
  • 39 Department of Genetics, Stanford University, Stanford, CA; Department of Biomedical Data Science, Stanford University, Stanford, CA
  • 40 Center for Inherited Cardiovascular Disease, Stanford Medicine, Stanford, CA
  • 41 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Lifera Omics, Riyadh, Saudi Arabia
  • 42 Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
  • 43 Broad Institute Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Neurology, Brigham and Women's Hospital, Boston, MA
  • 44 Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: Nic.Robertson@ed.ac.uk
  • 45 Broad Institute Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada. Electronic address: glemiret@broadinstitute.org
Genet Med, 2026 Oct;28(10):102633.
PMID: 42322193 DOI: 10.1016/j.gim.2026.102633

Abstract

PURPOSE: We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing (RNA-seq) for variant classification, and highlight the challenges in detecting variants in this noncoding gene.

METHODS: Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals.

RESULTS: We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions, and immune deficiency. Additional findings, such as diabetes, holoprosencephaly, and the absence of various core features in some individuals, highlight the broad phenotypic spectrum. All individuals who underwent RNA-seq showed a consistent pattern of minor intron retention. In 6 individuals, RNA-seq enabled the reclassification of variants of uncertain significance as likely pathogenic. Although RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis because of their noncoding nature.

CONCLUSION: This study highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

MeSH terms
Similar publications