ArticleGenetics in medicine : official journal of the American College of Medical Genetics2026
RNU4ATAC-opathy: Clinical, molecular, and transcriptomic insights from a large cohort.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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70 authors.
Dena R MatalonDivision of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA. Electronic address: matalon@stanford.edu.
Angela L DukerDivision of Orthogenetics, Department of Pediatrics, Nemours Children's Hospital, Wilmington, DE.
Taylor M ArriagaDepartment of Genetics, Stanford University, Stanford, CA.
Kathryn RussellBroad Institute Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Hector Rodrigo MendezDepartment of Medicine, Stanford University, Standford, CA.
Devon E BonnerDivision of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA.
Margaret E HarleyMedical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.
Moriel Singer-BerkBroad Institute Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Monica H WojcikBroad 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.
Lynn PaisBroad Institute Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Stephanie DiTroiaBroad Institute Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Melanie O'LearyBroad Institute Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Thomas CassiniVanderbilt University Medical Center, Nashville, TN.
Kimberly EzellVanderbilt University Medical Center, Nashville, TN.
Anne D NiehausDivision of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA.
Julie KaplanCleveland Clinic Foundation, Cleveland, OH.
David S WargowskiDivision of Genetics and Metabolism, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Cory J SmidDivision of Genetics and Metabolism, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Emily D LongeneckerDivision of Orthogenetics, Department of Pediatrics, Nemours Children's Hospital, Wilmington, DE.
Ana Maria Rodriguez BarretoDivision of clinical genetics, Nicklaus Children's Hospital, Miami, FL.
Danny E MillerDivision 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.
Alexandra C KeefeDivision of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA.
Laurel CalderwoodDivision of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA.
Gregory M EnnsDivision of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA.
Mustafa TekinJohn T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL.
Stephanie A BivonaJohn T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL.
Neeta L VoraObstetrics and Gynecology; Division of Maternal Fetal Medicine, UNC Chapel Hill School of Medicine, Chapel Hill, NC.
Kelly L GilmoreObstetrics and Gynecology; Division of Maternal Fetal Medicine, UNC Chapel Hill School of Medicine, Chapel Hill, NC.
Tahir N KhanStanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
Erica E DavisStanley 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.
Amber W WangORIC Pharmaceuticals, South San Francisco, CA.
Sameena KhanDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Sateesh MaddirevulaPrecision 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.
Lama Al AbdiDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Omar AbuyousefDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Hanan E ShamseldinDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Salwa AlkhalifiNewborn Screening program, Ministry of Health, Eastern Province, Saudi Arabia.
Firdous AbdulwahabDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Mashael AlqahtaniDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Zainab A AlhumaidiNewborn Screening program, Ministry of Health, Eastern Province, Saudi Arabia.
Seba NadeefDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Amal M Al HashemDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Khadijah BakurLifera Omics, Riyadh, Saudi Arabia.
Eissa A FaqeihSection of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
Ebtesam AbdallaHuman Genetics Department, Medical Research Institute, Alexandria University, Alexandria Egypt.
Angus ClarkeDivision of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom.
Elaine FletcherDepartment of Clinical Genetics, Centre for Genomic and Experimental Medicine, Western General Hospital, Crewe Road South, Edinburgh, United Kingdom.
Wee Teik KengDepartment of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.
Lilian Bomme OusagerDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Deepthi C de SilvaDepartment of Physiology, Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka.
Muzhirah HaniffaDepartment of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.
Francesca MariDepartment of Medicine, Surgery and Neurosciences, University of Siena, Italy and Clinical Pathology Unit, University Hospital of Siena, Siena, Italy.
Wayne LamSouth East of Scotland Clinical Genetics Service, Edinburgh, United Kingdom.
Jennifer CampbellClinical Genomics Service, Leeds Teaching Hospitals National Health Service Trust, Leeds, United Kingdom.
Tessa HomfrayMedical Genetics Service, St George's University Hospital and Royal Brompton Hospital London, London, United Kingdom.
Sheela NampoothiriDepartment of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Kochi, India.
Chumei LiDepartment of Paediatrics, McMaster University Medical Center, Hamilton, ON, Canada.
Bimal P ChaudhariDivision of Genetics and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
Kristen TruxalDivision of Genetics and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
Genomics Research to Elucidate the Genetics of Rare Diseases consortium, Undiagnosed Diseases Network
Jonathan A BernsteinDepartment of Pediatrics, Stanford University School of Medicine, Stanford University, Stanford, CA.
Stephen B MontgomeryDepartment of Genetics, Stanford University, Stanford, CA; Department of Biomedical Data Science, Stanford University, Stanford, CA.
Matthew T WheelerCenter for Inherited Cardiovascular Disease, Stanford Medicine, Stanford, CA.
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Lifera Omics, Riyadh, Saudi Arabia.
Anne O'Donnell-LuriaBroad 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.
Andrew P JacksonMedical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.
Ian M CampbellDivision of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Vijay S GaneshBroad 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.
Nic RobertsonMedical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: Nic.Robertson@ed.ac.uk.
Gabrielle LemireBroad 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.
Funding
Stanford Mendelian Genomics Research CenterU01HG011762 · NHGRI · STANFORD UNIVERSITY · PI Jonathan Adam Bernstein, Stephen Montgomery · 2021 to 2026
$16.7MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MBroad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6MVanderbilt Center for Undiagnosed Diseases (VCUD) - BiorepositoryU01HG007674 · NHGRI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI COGAN, JOY D, HAMID, RIZWAN · 2014 to 2022
$13.7MWhat comes next? Engaging stakeholders in governance of participant data and relationships during the sunset of large genomic medicine research initiativesU01HG010218 · NHGRI · STANFORD UNIVERSITY · PI ASHLEY, EUAN A, BERNSTEIN, JONATHAN ADAM · 2018 to 2022
$6.3MUnmet Needs: Achieving Equity and Support for Parents Pursuing Prenatal Diagnosis in the Genomic EraR01HD105868 · NICHD · UNIV OF NORTH CAROLINA CHAPEL HILL · PI VORA, NEETA L · 2021 to 2025
$3.4MCenter for Undiagnosed Diseases at StanfordU01NS134358 · NINDS · STANFORD UNIVERSITY · PI Jonathan Adam Bernstein, HOLLY K TABOR · 2023 to 2026
$3.1MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MExploring minorities The Undiagnosed Diseases Network Clinical Site of MiamiU01HG010230 · NHGRI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI TEKIN, MUSTAFA, ZUCHNER, STEPHAN · 2018 to 2021
$2.6MLong-read DNA and RNA sequencing to identify disease-causing genetic variation and streamline testingDP5OD033357 · OD · UNIVERSITY OF WASHINGTON · PI MILLER, DANNY ERWIN · 2022 to 2025
$1.9MIntegrating multiomic analyses for gene discovery andgenetic diagnosis of Mendelian myopathiesK23AR083505 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI Vijay S Ganesh · 2024 to 2026
$522kC BRIGGSAE AND C ELEGANS GENOMIC SEQUENCE COMPARISONF32HG000130 · NHGRI · WASHINGTON UNIVERSITY · PI COUCH, JENNIFER A · 1994 to 1995
–NHGRI NIH HHS F32 HG000130NHGRI NIH HHS R01 HG009141NHGRI NIH HHS U01 HG007674NHGRI NIH HHS U01 HG010218NHGRI NIH HHS U01 HG010230NHGRI NIH HHS U01 HG011755NHGRI NIH HHS U01 HG011762NHGRI NIH HHS UM1 HG008900NIAMS NIH HHS K23 AR083505NICHD NIH HHS R01 HD105868NIH HHS DP5 OD033357NINDS NIH HHS U01 NS134358
Abstract
purposeWe 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.
methodsSixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals.
resultsWe 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.
conclusionThis 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.
Indexed as
Lowry-Wood syndromeMinor spliceosomeMOPD type 1RNU4ATACRoifman syndrome
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