ArticleNature genetics2017
SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
Erratum issuedOpen access · greenAbstract read
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Article in Nature genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 92 papers.
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92citing papers in PubMed
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Who cites it
92 citing papers in PubMed, 160 citations in OpenAlex.
- Genetics of Idiopathic Hypogonadotropic HypogonadismJournal of clinical research in pediatric endocrinology · 2026Review
- Selective interaction of SMCHD1 with chromatin is governed by LRIF1 and SMCHD1 ATPase activity.Nature communications · 2026Article
- Cranial placode differentiation defect in individuals born without a nose.Stem cell reports · 2026Article
- Complete genetic and epigenetic architecture of D4Z4 macrosatellites in FSHD, BAMS, and reference cohorts with D4Z4End2End.Genome research · 2026Article
- CEP76 impairment at the centrosome-cilium interface contributes to a spectrum of ciliopathies.Science advances · 2025Article
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- SMCHD1 genetic variants in type 2 facioscapulohumeral dystrophy and challenges in predicting pathogenicity and disease penetrance.European journal of human genetics : EJHG · 2025Article
- RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.Nature communications · 2025Article
- SIX transcription factors are necessary for the activation of DUX4 expression in facioscapulohumeral muscular dystrophy.Skeletal muscle · 2024Article
- An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants.JCI insight · 2024Article
- Prenatal detection of distal 18p deletion by chromosomal microarray analysis: Three case reports and literature review.Medicine · 2024Review
- DNMT3B splicing dysregulation mediated by SMCHD1 loss contributes to DUX4 overexpression and FSHD pathogenesis.Science advances · 2024Article
- Identification of a pathogenic SMCHD1 variant in a Chinese patient with bosma arhinia microphthalmia syndrome: a case report.BMC medical genomics · 2024Article
- Engineered FSHD mutations results in D4Z4 heterochromatin disruption and feedforward DUX4 network activation.iScience · 2024Article
- Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development.Nature communications · 2024Article
- DigenicHeliyon · 2024Article
- SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease.Nature communications · 2023Article
- In skeletal muscle and neural crest cells, SMCHD1 regulates biological pathways relevant for Bosma syndrome and facioscapulohumeral dystrophy phenotype.Nucleic acids research · 2023Article
- SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.Communications biology · 2023Article
- Facial analytics based on a coordinate extrapolation system (zFACE) for morphometric phenotyping of developing zebrafish.Disease models & mechanisms · 2023Article
32 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
78 authors at 20 institutions in 11 countries.
Natalie D ShawHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Harrison BrandHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Zachary A KupchinskyCenter for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
Hemant BenganiMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
Lacey PlummerHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Takako I JonesDepartment of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Serkan ErdinMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.ORCID http://orcid.org/0000-0001-6587-2625
Kathleen A WilliamsonMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
Joe RaingerMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
Alexei StortchevoiMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Kaitlin SamochaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Benjamin B CurrallMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Donncha S DunicanMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
Ryan L CollinsMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.ORCID http://orcid.org/0000-0003-1268-9995
Jason R WillerCenter for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
Angela LekDepartment of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Monkol LekProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Malik NassanDepartment of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.
Shahrin PereiraDepartment of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Tammy KamminDepartment of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Diane LucenteMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Alexandra SilvaMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Catarina M SeabraMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Colby ChiangMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.ORCID http://orcid.org/0000-0002-4113-6065
Yu AnMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Morad AnsariMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
Jacqueline K RaingerMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
Shelagh JossWest of Scotland Genetics Service, South Glasgow University Hospitals, Glasgow, UK.
Jill Clayton SmithFaculty of Medical and Human Sciences, Institute of Human Development, Manchester Centre for Genomic Medicine, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK.
Margaret F LippincottHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Sylvia S SinghHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Nirav PatelHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Jenny W JingHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Jennifer R LawDivision of Pediatric Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nalton FerraroDepartment of Oral and Maxillofacial Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.
Alain VerloesDepartment of Genetics, Robert Debré Hospital, Paris, France.
Anita RauchInstitute of Medical Genetics and Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, Switzerland.
Katharina SteindlInstitute of Medical Genetics and Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, Switzerland.
Markus ZweierInstitute of Medical Genetics and Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, Switzerland.
Ianina ScheerDepartment of Diagnostic Imaging, Children's Hospital, Zurich, Switzerland.
Daisuke SatoDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Nobuhiko OkamotoDepartment of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
Christina JacobsenDivision of Endocrinology and Genetics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Jeanie TryggestadDepartment of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Steven ChernausekDepartment of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Lisa A SchimmentiDepartments of Otorhinolaryngology and Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.
Benjamin BrasseurDeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
Claudia CesarettiMedical Genetics Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
Jose E García-OrtizDivisión de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico.
Tatiana Pineda BuitragoFundación Hospital Infantil Universitario de San José, Bogotá, Colombia.
Orlando Perez SilvaAcademia Nacional de Medicina de Colombia, Bogotá, Colombia.
Jodi D HoffmanDivisions of Genetics and Maternal Fetal Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
Wolfgang MühlbauerDepartment of Plastic and Aesthetic Surgery, ATOS Klinik, Munich, Germany.
Klaus W RuprechtDepartment of Ophthalmology, University Hospital of the Saarland, Homburg, Germany.
Bart L LoeysCenter for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Masato ShinoDepartment of Otolaryngology and Head and Neck Surgery, Gunma University Graduate School of Medicine, Gunma, Japan.
Angela M KaindlBiology and Neurobiology, Charité-University Medicine Berlin and Berlin Institute of Health, Berlin, Germany.
Chie-Hee ChoDepartment of Diagnostic, Interventional and Pediatric Radiology, Inselspital, University Hospital of Bern, Bern, Switzerland.
Cynthia C MortonProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.ORCID http://orcid.org/0000-0003-2198-6756
Richard R MeehanMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
Veronica van HeyningenMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
Eric C LiaoCenter for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Ravikumar BalasubramanianHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Janet E HallHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Stephanie B SeminaraHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Daniel MacarthurProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Steven A MooreDepartment of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Koh-Ichiro YoshiuraDepartment of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
James F GusellaMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Joseph A MarshMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.ORCID http://orcid.org/0000-0003-4132-0628
John M GrahamDepartment of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California, USA.
Angela E LinMedical Genetics, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts, USA.
Nicholas KatsanisCenter for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
Peter L JonesDepartment of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
William F CrowleyHarvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Erica E DavisCenter for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
David R FitzPatrickMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
Michael E TalkowskiMolecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Massachusetts General Hospital · USWestern General Hospital · GBBroad Institute · USDuke Medical Center · USHarvard University · USUniversity of Zurich · CHBoston Children's Hospital · USBrigham and Women's Hospital · USUniversity of Massachusetts Chan Medical School · USUniversity of Oklahoma Health Sciences Center · USBerlin Institute of Health at Charité - Universitätsmedizin Berlin · DECedars-Sinai Medical Center · USFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico · ITGunma University · JPHokkaido University · JPHôpital Robert-Debré · FRHospital Universitario Infantil San José · COManchester Academic Health Science Centre · GBMayo Clinic · USMayo Clinic in Florida · US
Funding
Harvard Clinical and Translational Science CenterUL1TR001102 · NCATS · HARVARD MEDICAL SCHOOL · PI NADLER, LEE MARSHALL · 2013 to 2017
$106.2MRAPID GENE DISCOVERYP01GM061354 · NIGMS · BRIGHAM AND WOMEN'S HOSPITAL · PI GUSELLA, JAMES F · 2001 to 2019
$24.3MTherapeutic Potential of ESC-Derived Myogenic PrecursorsU54NS053672 · NINDS · UNIVERSITY OF IOWA · PI MATHEWS, KATHERINE DIANNE · 2005 to 2019
$22.0MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MMyogenesis Studies for FSHD BiomarkersU54HD060848 · NICHD · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI EMERSON, CHARLES P. · 2008 to 2017
$16.1MThe Genetic Determinants of Human GNRH DeficiencyP50HD028138 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI CROWLEY, WILLIAM FRANCIS · 2014 to 2020
$12.9MClinical Diagnostic Sequencing of Structural VariationR01HD081256 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2015 to 2025
$7.2MKisspeptin Physiology in the HumanR01HD043341 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI SEMINARA, STEPHANIE BETH · 2003 to 2019
$6.3MMechanisms of DUX4 mediated FSHD pathologyR01AR062587 · NIAMS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI JONES, PETER L · 2013 to 2024
$5.3MResearch Project 3P50DK096415 · NIDDK · DUKE UNIVERSITY · PI HAUSER, MICHAEL A · 2012 to 2016
$4.2MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MTRAINING PROGRAM IN REPRODUCTIVE &DEVELOPMENTAL BIOLOGYT32HD007396 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI CROWLEY, WILLIAM FRANCIS · 1991 to 2018
$2.5MMedical Research Council MC_PC_U127527199Medical Research Council MC_PC_U127561093Medical Research Council MC_PC_U127574433Medical Research Council MC_U127527199Medical Research Council MC_U127561093Medical Research Council MR/M02122X/1NCATS NIH HHS UL1 TR001102NHGRI NIH HHS UM1 HG008900NIAMS NIH HHS R01 AR062587NICHD NIH HHS F32 HD085857NICHD NIH HHS K23 HD073304NICHD NIH HHS K23 HD077043NICHD NIH HHS P50 HD028138NICHD NIH HHS R01 HD043341NICHD NIH HHS R01 HD081256NICHD NIH HHS T32 HD007396NICHD NIH HHS U54 HD060848NIDDK NIH HHS P50 DK096415NIGMS NIH HHS P01 GM061354NIMH NIH HHS R00 MH095867NINDS NIH HHS U54 NS053672
Abstract
Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.
Indexed as
AdolescentChildChild, PreschoolChoanal AtresiaChromosomal Proteins, Non-HistoneFemaleGenetic Predisposition to DiseaseHumansInfantMaleMicrophthalmosMuscular DystrophiesMutationNosePhenotypeChromosomal Proteins, Non-HistoneSMCHD1 protein, human
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