title: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
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.
authors.affiliation: Harvard 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.|National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
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authors.affiliation: Harvard 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.|Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
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authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
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authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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authors.identifier: http://orcid.org/0000-0001-6587-2625
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
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authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
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authors.identifier: http://orcid.org/0000-0003-1268-9995
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
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authors.identifier: http://orcid.org/0000-0003-2198-6756
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authors.affiliation: Harvard 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.|National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
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authors.initials: SB
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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authors.initials: D
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authors.initials: SA
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authors.initials: KI
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authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
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authors.initials: JF
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authors.identifier: http://orcid.org/0000-0003-4132-0628
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authors.initials: AE
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authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
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authors.initials: N
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authors.initials: PL
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authors.affiliation: Harvard 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.
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Michael E
authors.initials: ME
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mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002754:Choanal Atresia / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008850:Microphthalmos / Q000235:genetics*; D009136:Muscular Dystrophies / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009666:Nose / Q000002:abnormalities*; D010641:Phenotype
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C578241:SMCHD1 protein, human