ArticleNature genetics2023
Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.
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Article in Nature genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 34 citations in OpenAlex.
- Mechanisms underlying disease-causing variants in promoters and enhancers.Nature genetics · 2026Review
- Distinct transcriptional programs define cranial motor neuron subtypes during vertebrate development.bioRxiv : the preprint server for biology · 2026Article
- Analysis of 14q12 microdeletions reveals novel regulatory loci for the neurodevelopmental disorder-related gene FOXG1.Nature communications · 2026Article
- Multimodality Craniofacial Phenotyping of Congenital Facial Weakness Disorders.The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association · 2026Article
- Paired DNA and RNA sequencing uncovers common and rare variation regulating human retinal gene expression.Nature communications · 2026Article
- Silencer variants are key drivers of gene up-regulation in Alzheimer's disease.Science advances · 2026Article
- Advances in scCUT&Tag and computational analysis for single-cell gene regulatory element mapping.Briefings in bioinformatics · 2026Review
- A combined genomic arrhythmia propensity score delineates cumulative risk.Cell reports. Medicine · 2025Article
- Article
- Systematic identification of disease-causing promoter and untranslated region variants in 8040 undiagnosed individuals with rare disease.Genome medicine · 2025Article
- Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Non-coding cis-regulatory variants in HK1 cause congenital hyperinsulinism with variable disease severity.Genome medicine · 2025Article
- Rapid and quantitative functional interrogation of human enhancer variant activity in live mice.Nature communications · 2025Article
- Systematic phenotype and genotype characterization of Moebius syndrome.Genetics in medicine open · 2025Article
- A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.Nature communications · 2024Article
- The contribution of silencer variants to human diseases.Genome biology · 2024Article
- Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities.Nature genetics · 2024Article
- Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.medRxiv : the preprint server for health sciences · 2024Article
- Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.medRxiv : the preprint server for health sciences · 2023Article
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Authors and funding
58 authors at 20 institutions in 8 countries.
Alan P Tenney *Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Silvio Alessandro Di Gioia *Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-7235-5682
Bryn D Webb *Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Wai-Man ChanDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-2888-4739
Elke de BoerDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.ORCID 0000-0002-7022-577X
Sarah J GarnaiDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-0283-5437
Brenda J BarryDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Tammy RayDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Michael KosickiEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Caroline D RobsonDepartment of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-5592-249X
Zhongyang ZhangDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-2521-3884
Thomas E CollinsDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Alon GelberDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Brandon M PrattDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-1509-7509
Yuko FujiwaraDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
Arushi VarshneyDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0001-9177-9707
Monkol LekDepartment of Genetics, Yale University School of Medicine, New Haven, CT, USA.ORCID 0000-0003-1227-6293
Peter E WarburtonDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Carol Van RyzinMetabolic Medicine Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Tanya J LehkyEMG Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
Christopher ZalewskiAudiology Unit, Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA.
Kelly A KingAudiology Unit, Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA.
Carmen C BrewerAudiology Unit, Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA.
Audrey ThurmNeurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, NIH, Bethesda, MD, USA.
Joseph SnowOffice of the Clinical Director, National Institute of Mental Health, NIH, Bethesda, MD, USA.
Flavia M FacioCenter for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Narisu NarisuCenter for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.ORCID 0000-0002-8483-1156
Lori L BonnycastleCenter for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Amy SwiftCenter for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Peter S ChinesCenter for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Jessica L BellDepartment of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-9563-0125
Suresh MohanDepartment of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-4797-9565
Mary C WhitmanF.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.ORCID 0000-0001-6297-7499
Sandra E StaffieriCentre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, and University of Melbourne, Melbourne, Victoria, Australia.ORCID 0000-0003-3131-9359
James E ElderDepartment of Ophthalmology, Royal Children's Hospital, Parkville, Victoria, Australia.
Joseph L DemerStein Eye Institute and Departments of Ophthalmology, Neurology, and Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.ORCID 0000-0001-9662-5352
Alcy TorresDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Elza RachidDepartment of Ophthalmology, American University of Beirut Medical Center, Beirut, Lebanon.ORCID 0000-0003-3756-0872
Christiane Al-HaddadDepartment of Ophthalmology, American University of Beirut Medical Center, Beirut, Lebanon.
Rose-Mary BoustanyPediatrics & Adolescent Medicine/Biochemistry & Molecular Genetics, American University of Beirut Medical Center, Beirut, Lebanon.ORCID 0000-0002-2066-0079
David A MackeyLions Eye Institute, University of Western Australia, Perth, Australia.
Angela F BradyNorth West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK.
María Fenollar-CortésUnidad de Genética Clínica, Instituto de Medicina del Laboratorio. IdISSC, Hospital Clínico San Carlos, Madrid, Spain.
Melanie FradinService de Génétique Clinique, CHU Rennes, Centre Labellisé Anomalies du Développement, Rennes, France.
Tjitske KleefstraDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
George W PadbergDepartment of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands.
Salmo RaskinCentro de Aconselhamento e Laboratório Genetika, Curitiba, Paraná, Brazil.ORCID 0000-0002-7191-0592
Mario Teruo SatoDepartment of Ophthalmology & Otorhinolaryngology, Federal University of Paraná, Curitiba, Paraná, Brazil.
Stuart H OrkinHoward Hughes Medical Institute, Chevy Chase, MD, USA.ORCID 0000-0002-0313-152X
Stephen C J ParkerDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0001-8122-0117
Tessa A HadlockDepartment of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
Lisenka E L M VissersDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.ORCID 0000-0001-6470-5497
Hans van BokhovenDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.ORCID 0000-0002-2153-9254
Ethylin Wang JabsDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0001-8983-5466
Francis S CollinsCenter for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Len A PennacchioEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.ORCID 0000-0002-8748-3732
Irini ManoliMetabolic Medicine Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.ORCID 0000-0003-1543-2941
Elizabeth C EngleDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. elizabeth.engle@childrens.harvard.edu.ORCID 0000-0001-8194-7738
Boston Children's Hospital · USNational Human Genome Research Institute · USRadboud University Nijmegen · NLAmerican University of Beirut Medical Center · LBIcahn School of Medicine at Mount Sinai · USNational Institute on Deafness and Other Communication Disorders · USLawrence Berkeley National Laboratory · USMassachusetts Eye and Ear Infirmary · USNational Institute of Mental Health · USRoyal Children's Hospital · AUUniversity of Michigan · USBoston Medical Center · USCIC Rennes · FRDana-Farber/Boston Children's Cancer and Blood Disorders Center · USHoward Hughes Medical Institute · USInstituto de Investigación Sanitaria del Hospital Clínico San Carlos · ESLions Eye Institute · AUNational Institute of Neurological Disorders and Stroke · USNorthwick Park Hospital · GBUniversidade Federal do Paraná · BR
Funding
Conduits: Mount Sinai Health System Translational Science HubUL1TR004419 · NCATS · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Rosalind J Wright · 2022 to 2026
$46.4MClinical Analysis Of Disorders Of Hearing And BalanceZIADC000064 · NIDCD · NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS · PI HERTZANO, RONNA · 2009 to 2025
$25.2MGeneration of an In Vivo Human Genome Transcriptional Enhancer DatasetR01HG003988 · NHGRI · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI Len Alexander Pennacchio · 2006 to 2026
$24.1MNeurodevelopmental and Behavioral Phenotyping ZICMH002961 · NIMH · NATIONAL INSTITUTE OF MENTAL HEALTH · PI THURM, AUDREY · 2017 to 2025
$12.6MGenetic Analysis and Manipulation Core (GAEC)P50HD105351 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI SCOTT Loren POMEROY, MUSTAFA SAHIN · 2021 to 2026
$9.4MMouse Neurodevelopmental Behavior CoreU54HD090255 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI FAGIOLINI, MICHELA · 2016 to 2020
$5.2MGenetics of Moebius syndrome and other congenital facial weakness disordersZIAHG200389 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI COLLINS, FRANCIS S. · 2013 to 2024
$4.9MBirth Defects: Moebius syndrome and related facial weakness disordersU01HD079068 · NICHD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI BROOKS, BRIAN PATRICK, ENGLE, ELIZABETH C. · 2014 to 2016
$1.1MIntramural NIH HHS ZIC MH002961NCATS NIH HHS UL1 TR004419NHGRI NIH HHS R01 HG003988NICHD NIH HHS P50 HD105351NICHD NIH HHS U01 HD079068NICHD NIH HHS U54 HD090255
Abstract
Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.
Indexed as
Facial ParalysisAnimalsGATA2 Transcription FactorMiceMotor NeuronsNeurogenesisNeurons, EfferentGata2 protein, mouseGATA2 Transcription Factor
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