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

• Published in: Nature genetics Vol. 49; no. 2; pp. 238 - 248
• Main Authors: Shaw, Natalie D, Brand, Harrison, Kupchinsky, Zachary A, Bengani, Hemant, Plummer, Lacey, Jones, Takako I, Erdin, Serkan, Williamson, Kathleen A, Rainger, Joe, Stortchevoi, Alexei, Samocha, Kaitlin, Currall, Benjamin B, Dunican, Donncha S, Collins, Ryan L, Willer, Jason R, Lek, Angela, Lek, Monkol, Nassan, Malik, Pereira, Shahrin, Kammin, Tammy, Lucente, Diane, Silva, Alexandra, Seabra, Catarina M, Chiang, Colby, An, Yu, Ansari, Morad, Rainger, Jacqueline K, Joss, Shelagh, Smith, Jill Clayton, Lippincott, Margaret F, Singh, Sylvia S, Patel, Nirav, Jing, Jenny W, Law, Jennifer R, Ferraro, Nalton, Verloes, Alain, Rauch, Anita, Steindl, Katharina, Zweier, Markus, Scheer, Ianina, Sato, Daisuke, Okamoto, Nobuhiko, Jacobsen, Christina, Tryggestad, Jeanie, Chernausek, Steven, Schimmenti, Lisa A, Brasseur, Benjamin, Cesaretti, Claudia, García-Ortiz, Jose E, Buitrago, Tatiana Pineda, Silva, Orlando Perez, Hoffman, Jodi D, Mühlbauer, Wolfgang, Ruprecht, Klaus W, Loeys, Bart L, Shino, Masato, Kaindl, Angela M, Cho, Chie-Hee, Morton, Cynthia C, Meehan, Richard R, van Heyningen, Veronica, Liao, Eric C, Balasubramanian, Ravikumar, Hall, Janet E, Seminara, Stephanie B, Macarthur, Daniel, Moore, Steven A, Yoshiura, Koh-ichiro, Gusella, James F, Marsh, Joseph A, Graham, John M, Lin, Angela E, Katsanis, Nicholas, Jones, Peter L, Crowley, William F, Davis, Erica E, FitzPatrick, David R, Talkowski, Michael E
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-02-2017; Nature Publishing Group
• Subjects: 631/136/1660; 631/208/207; 631/208/212; Adolescent; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Child; Child, Preschool; Choanal Atresia - genetics; Chromosomal Proteins, Non-Histone - genetics; Consortia; Defects; Dystrophy; Female; Gene expression; Gene Function; Gene mutation; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genomes; Health aspects; Human Genetics; Humans; Infant; Informatics; Male; Medical research; Microphthalmos; Microphthalmos - genetics; Muscular Dystrophies - genetics; Muscular dystrophy; Mutation; Mutation - genetics; Nose - abnormalities; Phenotype; Phenotypes; Proteins; Risk factors; Studies; Zebrafish
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3743

Michael Talkowski, David FitzPatrick, Erica Davis and colleagues report rare inherited or
de novo
missense variants in
SMCHD1
in arhinia patients. Some of the same mutations in
SMCHD1
are known to cause a phenotypically distinct muscular dystrophy disorder, FSHD2, and the distinct clinical features of the two disorders suggests that additional genes interact with
SMCHD1
to cause arhinia.
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.