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

Natalie D. Shaw, Harrison Brand, Zachary A. Kupchinsky, Hemant Bengani, Lacey Plummer, Takako I. Jones, Serkan Erdin, Kathleen A. Williamson, Joe Rainger, Alexei Stortchevoi, Kaitlin Samocha, Benjamin B. Currall, Donncha S. Dunican, Ryan L. Collins, Jason R. Willer, Angela Lek, Monkol Lek, Malik Nassan, Shahrin Pereira, Tammy KamminDiane Lucente, Alexandra Silva, Catarina M. Seabra, Colby Chiang, Yu An, Morad Ansari, Jacqueline K. Rainger, Shelagh Joss, Jill Clayton Smith, Margaret F. Lippincott, Sylvia S. Singh, Nirav Patel, Jenny W. Jing, Jennifer R. Law, Nalton Ferraro, Alain Verloes, Anita Rauch, Katharina Steindl, Markus Zweier, Ianina Scheer, Daisuke Sato, Nobuhiko Okamoto, Christina Jacobsen, Jeanie Tryggestad, Steven Chernausek, Lisa A. Schimmenti, Benjamin Brasseur, Claudia Cesaretti, Jose E. Garciá-Ortiz, Tatiana Pineda Buitrago, Orlando Perez Silva, Jodi D. Hoffman, Wolfgang Mühlbauer, Klaus W. Ruprecht, Bart L. Loeys, Masato Shino, Angela M. Kaindl, Chie Hee Cho, Cynthia C. Morton, Richard R. Meehan, Veronica Van Heyningen, Eric C. Liao, Ravikumar Balasubramanian, Janet E. Hall, Stephanie B. Seminara, Daniel MacArthur, Steven A. Moore, Koh Ichiro Yoshiura, James F. Gusella, Joseph A. Marsh, John M. Graham, Angela E. Lin, Elias Nicholas Katsanis, Peter L. Jones, William F. Crowley, Erica Ellen Davis, David R. Fitzpatrick, Michael E. Talkowski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)238-248
Number of pages11
JournalNature Genetics
Issue number2
StatePublished - Jan 31 2017

ASJC Scopus subject areas

  • Genetics


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