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Nat Genet. 2017 Feb;49(2):238-248. doi: 10.1038/ng.3743. Epub 2017 Jan 9.

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Author information

1
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.
2
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
3
Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
4
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
5
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
6
Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
7
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
8
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
9
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
10
Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
11
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
12
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.
13
Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
14
GABBA Program, University of Porto, Porto, Portugal.
15
West of Scotland Genetics Service, South Glasgow University Hospitals, Glasgow, UK.
16
Faculty 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.
17
Division of Pediatric Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
18
Department of Oral and Maxillofacial Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.
19
Department of Genetics, Robert Debré Hospital, Paris, France.
20
Institute of Medical Genetics and Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, Switzerland.
21
Department of Diagnostic Imaging, Children's Hospital, Zurich, Switzerland.
22
Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
23
Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
24
Division of Endocrinology and Genetics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
25
Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
26
Departments of Otorhinolaryngology and Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.
27
DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
28
Medical Genetics Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
29
División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico.
30
Fundación Hospital Infantil Universitario de San José, Bogotá, Colombia.
31
Academia Nacional de Medicina de Colombia, Bogotá, Colombia.
32
Divisions of Genetics and Maternal Fetal Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
33
Department of Plastic and Aesthetic Surgery, ATOS Klinik, Munich, Germany.
34
Department of Ophthalmology, University Hospital of the Saarland, Homburg, Germany.
35
Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
36
Department of Otolaryngology and Head and Neck Surgery, Gunma University Graduate School of Medicine, Gunma, Japan.
37
Biology and Neurobiology, Charité-University Medicine Berlin and Berlin Institute of Health, Berlin, Germany.
38
Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, University Hospital of Bern, Bern, Switzerland.
39
Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
40
Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
41
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
42
Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
43
Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
44
Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
45
Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California, USA.
46
Medical Genetics, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts, USA.

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.

PMID:
28067909
PMCID:
PMC5473428
DOI:
10.1038/ng.3743
[Indexed for MEDLINE]
Free PMC Article

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