De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

CT Gordon; S Xue; G Yigit; H Filali; K Chen; N Rosin; KI Yoshiura; M Oufadem; TJ Beck; R McGowan; AC Magee; J Altmüller; C Dion; H Thiele; AD Gurzau; P Nürnberg; D Meschede; W Mühlbauer; N Okamoto; V Varghese; R Irving; S Sigaudy; D Williams; SF Ahmed; C Bonnard; MK Kong; I Ratbi; N Fejjal; M Fikri; SC Elalaoui; H Reigstad; C Bole-Feysot; P Nitschké; N Ragge; N Lévy; G Tunçbilek; ASM Teo; ML Cunningham; A Sefiani; H Kayserili; JM Murphy; C Chatdokmaiprai; AM Hillmer; D Wattanasirichaigoon; S Lyonnet; F Magdinier; A Javed; ME Blewitt; J Amiel; B Wollnik; B Reversade

Journal article

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

CT Gordon, S Xue, G Yigit, H Filali, K Chen, N Rosin, KI Yoshiura, M Oufadem, TJ Beck, R McGowan, AC Magee, J Altmüller, C Dion, H Thiele, AD Gurzau, P Nürnberg, D Meschede, W Mühlbauer, N Okamoto, V Varghese Show all

Nature Genetics | NATURE PUBLISHING GROUP | Published : 2017

DOI: 10.1038/ng.3765

Abstract

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results ..

View full abstract

University of Melbourne Researchers

Alexandra Gurzau Author

James Murphy Author

Marnie Blewitt Author

Grants

Awarded by National Science Foundation

Funding Acknowledgements

We would like to thank all family members and their relatives for their participation and kind contribution to this study. N. Akarsu was instrumental for recruiting patient 11. Support from the Jean Renny Endowed Chair for Craniofacial Research (M.L.C.) is acknowledged. C.D. is the recipient of a fellowship from the French Ministry of Education and Research. H.F. was supported by a postdoctoral grant from INSERM. B.R. is a fellow of the Branco Weiss Foundation, an AstarSTAR Investigator, an EMBO Young Investigator and a recipient of the inaugural AAA Fellowship in Amsterdam. This work was supported by funding from the Agence Nationale de la Recherche (ANR-10-IAHU-01, CranioRespiro), the Cancer Council Victoria (fellowship to K.C.), the National Health and Medical Research Council (NHMRC) of Australia to M.E.B. and J.M.M. (1098290 and fellowships 1110206 and 1105754), the Scientific and Technological Research Council of Turkey (TUBITAK) to H.K. (grant 112S398, E-RARE network CRANIRARE-2), the Association Francaise contre les Myopathies (AFM) to F.M., Victorian State Government Operational Infrastructure Support, an NHMRC TRUSS grant (9000220), the German Federal Ministry of Education and Research (BMBF) to B.W. (grant 01GM1211A, E-RARE network CRANIRARE-2), the German Research Foundation (SFB1002, project D02) to B.W., MACS, VICTA and Baillie Gifford grant support to N. Ragge, Mahidol University and Research Career Development Awards from the Faculty of Medicine Ramathibodi Hospital to D. Wattanasirichaigoon, an AstarSTAR JCO Career Development grant to A.J., an AstarSTAR BMRC Young Investigator Grant to S.X. and a Strategic Positioning Fund on Genetic Orphan Diseases from the Biomedical Research Council, AstarSTAR, Singapore, to B.R.