Linking genetic mutations to two rare facial conditions



Arhinia, or the complete absence of the external nose, is an extremely rare congenital malformation with fewer than 100 reported cases in the past century. The presence of several familial cases of arhinia raised suspicion for a genetic cause, but no previous studies had identified a plausible candidate gene.


An international team of researchers led by IRP investigator Natalie D. Shaw, M.D., MMSc., used whole-exome sequencing to search for a gene linked to arhinia in 40 patients with the condition. They discovered that 84% of the patients had a mutation in the gene SMCHD1, which encodes an epigenetic repressor. Surprisingly, identical mutations in SMCHD1 have previously been implicated in a rare form of muscular dystrophy called FSHD2, which is not associated with any facial deformities but does cause weakening and deterioration of the facial muscles. These data suggest that arhinia is driven not only by SMCHD1 mutations but also by other genetic and/or environmental factors yet to be identified.


This is the first study to identify a genetic cause of congenital arhinia. Work is now in progress to determine how SMCHD1 mutations interfere with craniofacial development and to identify the key genetic factors that differentiate arhinia from FSHD2.


Shaw ND, Brand H, Kupchinsky ZA, Bengani H, Plummer L, Jones TI, Erdin S, Williamson KA, Rainger J, Stortchevoi A, Samocha K, Currall BB, Dunican DS, Collins RL, Willer JR, Lek A, Lek M, Nassan M, Pereira S, Kammin T, Lucente D, Silva A, Seabra CM, Chiang C, An Y, Ansari M, Rainger JK, Joss S, Smith JC, Lippincott MF, Singh SS, Patel N, Jing JW, Law JR, Ferraro N, Verloes A, Rauch A, Steindl K, Zweier M, Scheer I, Sato D, Okamoto N, Jacobsen C, Tryggestad J, Chernausek S, Schimmenti LA, Brasseur B, Cesaretti C, García-Ortiz JE, Buitrago TP, Silva OP, Hoffman JD, Mühlbauer W, Ruprecht KW, Loeys BL, Shino M, Kaindl AM, Cho CH, Morton CC, Meehan RR, van Heyningen V, Liao EC, Balasubramanian R, Hall JE, Seminara SB, Macarthur D, Moore SA, Yoshiura KI, Gusella JF, Marsh JA, Graham JM Jr, Lin AE, Katsanis N, Jones PL, Crowley WF Jr, Davis EE, FitzPatrick DR, Talkowski ME. (2017). SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat. Genet. Feb;49:238-248.

View All Health Topics

This page was last updated on Tuesday, June 13, 2023