SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome
Creators: name: Lek, Monkol
name: Bengani, Hemant
name: Marsh, Joseph A.
name: Kaindl, Angela M.
name: Yoshiura, Koh-Ichiro
name: Steindl, Katharina
name: Ansari, Morad
name: Jing, Jenny W.
name: Singh, Sylvia S.
name: Ferraro, Nalton
name: Hall, Janet E.
name: Seminara, Stephanie B.
name: Seabra, Catarina M.
name: Graham, John M.
name: Jones, Takako I.
name: Okamoto, Nobuhiko
name: Liao, Eric C.
name: Moore, Steven A.
name: Jones, Peter L.
name: Hoffman, Jodi D.
name: Smith, Jill Clayton
name: Chernausek, Steven
name: Joss, Shelagh
name: Mühlbauer, Wolfgang
name: Kammin, Tammy
name: Nassan, Malik
name: Brasseur, Benjamin
name: MacArthur, Daniel
name: Davis, Erica E.
name: Collins, Ryan L.
name: Shaw, Natalie D.
name: Chiang, Colby
name: Brand, Harrison
name: Silva, Alexandra
name: Lin, Angela E.
name: An, Yu
name: Schimmenti, Lisa A.
name: Katsanis, Nicholas
name: Erdin, Serkan
name: Kupchinsky, Zachary A.
name: Van Heyningen, Veronica
name: Tryggestad, Jeanie
name: Morton, Cynthia C.
name: Rainger, Joe
name: Talkowski, Michael E.
name: Plummer, Lacey
name: Pereira, Shahrin
name: Cesaretti, Claudia
name: Dunican, Donncha S.
name: Buitrago, Tatiana Pineda
name: Cho, Chie-Hee
name: Meehan, Richard R.
name: Fitzpatrick, David R.
name: Willer, Jason R.
name: Verloes, Alain
name: Stortchevoi, Alexei
name: Lek, Angela
name: Gusella, James F.
name: Balasubramanian, Ravikumar
name: Sato, Daisuke
name: Crowley, William F.
name: Samocha, Kaitlin
name: Loeys, Bart L.
name: Lucente, Diane
name: Williamson, Kathleen A.
name: Patel, Nirav
name: Shino, Masato
name: Law, Jennifer R.
name: Zweier, Markus
name: Lippincott, Margaret F.
name: Currall, Benjamin B.
name: Jacobsen, Christina
name: Rainger, Jacqueline K.
name: Garciá-Ortiz, Jose E.
name: Silva, Orlando Perez
name: Scheer, Ianina
name: Rauch, Anita
name: Ruprecht, Klaus W.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2017

description: 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.