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

Nature Genetics volume 49, pages 238–248 (2017)Cite this article

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A Corrigendum to this article was published on 26 May 2017

This article has been updated

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.

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Figure 1: Phenotypic spectra associated with arhinia.
Figure 2: Association analyses for rare mutation burden in arhinia Manhattan plot and quantile-quantile (q-q) plot demonstrating the significant accumulation of rare SMCHD1 mutations in subjects with arhinia compared to the ExAC cohort (P = 2.9 × 10−17, Fisher's exact test; OR = 34.4 (95 CI: 18.8–57.9)).
Figure 3: Arhinia-associated mutations occur near the 5′ GHKL-type ATPase domain.
Figure 4: DNA methylation analysis of D4Z4 repeats.
Figure 5: In vivo modeling of smchd1 in zebrafish.
Figure 6: SMCHD1 protein modeling predicts that arhinia-associated alterations are more likely to occur on the surface of SMCHD1 and disrupt a binding surface than are FSHD2-associated variations.

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Change history

  • 20 March 2017

    In the version of this article initially published, the legend to Figure 4c stated that only one proband without SMCHD1 mutation was tested for D4Z4 methylation pattern. However, three probands and one affected family member without SMCHD1 mutation were tested, as shown in the figure. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank all participants, family members and clinical staff for their generous contributions of time and materials to this research. We thank T. Gillis, J. Ruliera, C. Hanscom, C. Antolik and M. Anderson for technical assistance. This project was funded by grants from the National Institutes of Health ((NIH) R00MH095867 and R01HD081256 to M.E.T.; P01GM061354 to M.E.T., J.F.G., C.C.M. and E.C.L.; T32HD007396 to H. Brand; P50HD028138 to W.F.C., S.B.S., M.E.T., N.K. and E.E.D.; R01HD043341 and MGH Robert and Laura Reynolds Research Scholar Award to S.B.S.; K23HD073304-02 and 1SI2ES025429-01 to N.D.S.; P50DK096415 to N.K. and R01AR062587 to P.L.J.); the March of Dimes (FY15-255 to M.E.T.); the Medical Research Council (MR/M02122X/1 to J.A.M.); the German Research Foundation (SFB665 to A.M.K.) and the Berlin Institute of Health (BIH-CRG1 to A.M.K.). D.R.F., R.R.M. (MC_PC_U127574433), D.S.D., H. Bengani, K.A.W., J.R., J.K.R. and J.A.M. are funded by program grants from the Medical Research Council (MRC) Human Genetics Unit award to the University of Edinburgh. M.A. is funded by the University of Edinburgh Institute of Genomics and Molecular Medicine Translational Initiative Fund. S.A.M. is supported by U54-NS053672, which funds the Iowa, Paul D. Wellstone Muscular Dystrophy Cooperative Research Center. N.K. is supported as a Distinguished Jean and George Brumley Professor at Duke University, and M.E.T. is supported as the Desmond and Ann Heathwood MGH Research Scholar.

Author information

Author notes

  1. Natalie D Shaw and Harrison Brand: These authors contributed equally to this work.

Authors and Affiliations

  1. Reproductive Endocrine Unit of the Department of Medicine, Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Massachusetts General Hospital, Boston, Massachusetts, USA

    Natalie D Shaw, Harrison Brand, Lacey Plummer, Margaret F Lippincott, Sylvia S Singh, Nirav Patel, Jenny W Jing, Ravikumar Balasubramanian, Janet E Hall, Stephanie B Seminara & William F Crowley Jr

  2. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

    Natalie D Shaw & Janet E Hall

  3. Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA

    Harrison Brand, Serkan Erdin, Alexei Stortchevoi, Benjamin B Currall, Ryan L Collins, Diane Lucente, Alexandra Silva, Catarina M Seabra, Colby Chiang, Yu An, James F Gusella & Michael E Talkowski

  4. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Harrison Brand, James F Gusella & Michael E Talkowski

  5. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Harrison Brand, Serkan Erdin, Kaitlin Samocha, Monkol Lek, Cynthia C Morton, Daniel Macarthur, James F Gusella & Michael E Talkowski

  6. Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA

    Zachary A Kupchinsky, Jason R Willer, Nicholas Katsanis & Erica E Davis

  7. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK

    Hemant Bengani, Kathleen A Williamson, Joe Rainger, Donncha S Dunican, Morad Ansari, Jacqueline K Rainger, Richard R Meehan, Veronica van Heyningen, Joseph A Marsh & David R FitzPatrick

  8. Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Takako I Jones & Peter L Jones

  9. Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Kaitlin Samocha, Monkol Lek & Daniel Macarthur

  10. Division of Medical Sciences, Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, Massachusetts, USA

    Ryan L Collins

  11. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Angela Lek & James F Gusella

  12. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA

    Malik Nassan

  13. Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Shahrin Pereira, Tammy Kammin & Cynthia C Morton

  14. GABBA Program, University of Porto, Porto, Portugal

    Catarina M Seabra

  15. West of Scotland Genetics Service, South Glasgow University Hospitals, Glasgow, UK

    Shelagh Joss

  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

    Jill Clayton Smith

  17. Division of Pediatric Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Jennifer R Law

  18. Department of Oral and Maxillofacial Surgery, Boston Children's Hospital, Boston, Massachusetts, USA

    Nalton Ferraro

  19. Department of Genetics, Robert Debré Hospital, Paris, France

    Alain Verloes

  20. Institute of Medical Genetics and Radiz–Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, Switzerland

    Anita Rauch, Katharina Steindl & Markus Zweier

  21. Department of Diagnostic Imaging, Children's Hospital, Zurich, Switzerland

    Ianina Scheer

  22. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Daisuke Sato

  23. Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan

    Nobuhiko Okamoto

  24. Division of Endocrinology and Genetics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Christina Jacobsen

  25. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Jeanie Tryggestad & Steven Chernausek

  26. Departments of Otorhinolaryngology and Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA

    Lisa A Schimmenti

  27. DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA

    Benjamin Brasseur

  28. Medical Genetics Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy

    Claudia Cesaretti

  29. División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico

    Jose E García-Ortiz

  30. Fundación Hospital Infantil Universitario de San José, Bogotá, Colombia

    Tatiana Pineda Buitrago

  31. Academia Nacional de Medicina de Colombia, Bogotá, Colombia

    Orlando Perez Silva

  32. Divisions of Genetics and Maternal Fetal Medicine, Tufts Medical Center, Boston, Massachusetts, USA

    Jodi D Hoffman

  33. Department of Plastic and Aesthetic Surgery, ATOS Klinik, Munich, Germany

    Wolfgang Mühlbauer

  34. Department of Ophthalmology, University Hospital of the Saarland, Homburg, Germany

    Klaus W Ruprecht

  35. Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium

    Bart L Loeys

  36. Department of Otolaryngology and Head and Neck Surgery, Gunma University Graduate School of Medicine, Gunma, Japan

    Masato Shino

  37. Biology and Neurobiology, Charité–University Medicine Berlin and Berlin Institute of Health, Berlin, Germany

    Angela M Kaindl

  38. Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, University Hospital of Bern, Bern, Switzerland

    Chie-Hee Cho

  39. Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Eric C Liao

  40. Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA

    Eric C Liao

  41. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA

    Eric C Liao

  42. Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Daniel Macarthur & Michael E Talkowski

  43. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    Steven A Moore

  44. Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Koh-ichiro Yoshiura

  45. Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California, USA

    John M Graham Jr

  46. Medical Genetics, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts, USA

    Angela E Lin

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Contributions

M.E.T., D.R.F., E.E.D., N.K., P.J., N.D.S. and H. Brand designed the study. N.D.S., L.P., K.A.W., M.N., S.P., T.K., D.L., A. Silva, S.J., J.C.S., M.F.L., S.S.S., N.P., J.R.L., N.F., A.V., A.R., K. Steindl, I.S., D.S., N.O., C.J., J.T., S.C., L.A.S., B.B., C. Cesaretti, J.E.G.-O., T.P.B., O.P.S., J.D.H., W.M., K.W.R., B.L.L., M.S., A.M.K., C.-H.C., C.C.M., V.v.H., R.B., J.E.H., S.B.S., K.Y., J.M.G., A.E.L., W.F.C. and D.R.F. recruited patients and collected clinical information and samples. Z.A.K., H. Bengani, L.P., S.E., T.I.J., J.R.W., J.R., A. Stortchevoi, C.M.S., Y.A., B.B.C., M.A., R.R.M., J.K.R., M.Z., J.W.J., E.C.L., S.A.M., N.K., P.L.J., E.E.D., D.R.F. and D.S.D. performed molecular genetics and animal modeling studies. H. Brand, K. Samocha, R.L.C., C. Chiang, A.L., M.L., J.F.G., D.G.M. and M.E.T. performed genomic analyses. J.A.M. performed protein modeling. N.D.S., H. Brand, N.K., J.F.G., P.L.J., E.E.D., D.R.F. and M.E.T. wrote the manuscript, which was revised and approved by all authors.

Corresponding authors

Correspondence to Erica E Davis, David R FitzPatrick or Michael E Talkowski.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 (PDF 5639 kb)

Supplementary Table 1

Arhina cohort-wide phenotype information. (XLSX 16 kb)

Supplementary Table 2

Individual level phenotype information. (XLSX 22 kb)

Supplementary Table 3

Ethnic specific analysis of SMCHD1 mutation frequency. (XLSX 9 kb)

Supplementary Table 4

DNA methylation analysis of D4Z4 repeats in arhinia cases and familial controls. (XLSX 17 kb)

Supplementary Table 5

Representative zebrafish morphometric data. (XLSX 21 kb)

Supplementary Table 6

Mouse CRISPR of SMCHD1 missense mutations. (XLSX 11 kb)

Supplementary Table 7

Allele-specific expression of SMCHD1 in subjects with a mutation. (XLSX 10 kb)

Supplementary Table 8

Differential expression analysis between arhinia cases and familial controls. (XLSX 1601 kb)

Supplementary Table 9

Enrichment of nominal human genes (P < 0.05) against mouse Smchd1 targets and differentially expressed genes in Smchd1-null mouse. (XLSX 10 kb)

Supplementary Table 10

Overlapping genes with significant dysregulation in the same direction in mouse and human. (XLSX 10 kb)

Supplementary Table 11

Primers used in study. (XLSX 11 kb)

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Shaw, N., Brand, H., Kupchinsky, Z. et al. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49, 238–248 (2017). https://doi.org/10.1038/ng.3743

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  • DOI: https://doi.org/10.1038/ng.3743

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