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

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  • A Corrigendum to this article was published on 26 May 2017


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.

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Figure 1: Phenotypic spectra associated with arhinia.
Figure 2: Association analyses for rare mutation burden in arhinia Manhattan plot and quantile-quantile (q-q) plot demonstrating the significant accumulation of rare SMCHD1 mutations in subjects with arhinia compared to the ExAC cohort (P = 2.9 × 10−17, Fisher's exact test; OR = 34.4 (95 CI: 18.8–57.9)).
Figure 3: Arhinia-associated mutations occur near the 5′ GHKL-type ATPase domain.
Figure 4: DNA methylation analysis of D4Z4 repeats.
Figure 5: In vivo modeling of smchd1 in zebrafish.
Figure 6: SMCHD1 protein modeling predicts that arhinia-associated alterations are more likely to occur on the surface of SMCHD1 and disrupt a binding surface than are FSHD2-associated variations.

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NCBI Reference Sequence

Protein Data Bank

Change history

  • 20 March 2017

    In the version of this article initially published, the legend to Figure 4c stated that only one proband without SMCHD1 mutation was tested for D4Z4 methylation pattern. However, three probands and one affected family member without SMCHD1 mutation were tested, as shown in the figure. The error has been corrected in the HTML and PDF versions of the article.


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We thank all participants, family members and clinical staff for their generous contributions of time and materials to this research. We thank T. Gillis, J. Ruliera, C. Hanscom, C. Antolik and M. Anderson for technical assistance. This project was funded by grants from the National Institutes of Health ((NIH) R00MH095867 and R01HD081256 to M.E.T.; P01GM061354 to M.E.T., J.F.G., C.C.M. and E.C.L.; T32HD007396 to H. Brand; P50HD028138 to W.F.C., S.B.S., M.E.T., N.K. and E.E.D.; R01HD043341 and MGH Robert and Laura Reynolds Research Scholar Award to S.B.S.; K23HD073304-02 and 1SI2ES025429-01 to N.D.S.; P50DK096415 to N.K. and R01AR062587 to P.L.J.); the March of Dimes (FY15-255 to M.E.T.); the Medical Research Council (MR/M02122X/1 to J.A.M.); the German Research Foundation (SFB665 to A.M.K.) and the Berlin Institute of Health (BIH-CRG1 to A.M.K.). D.R.F., R.R.M. (MC_PC_U127574433), D.S.D., H. Bengani, K.A.W., J.R., J.K.R. and J.A.M. are funded by program grants from the Medical Research Council (MRC) Human Genetics Unit award to the University of Edinburgh. M.A. is funded by the University of Edinburgh Institute of Genomics and Molecular Medicine Translational Initiative Fund. S.A.M. is supported by U54-NS053672, which funds the Iowa, Paul D. Wellstone Muscular Dystrophy Cooperative Research Center. N.K. is supported as a Distinguished Jean and George Brumley Professor at Duke University, and M.E.T. is supported as the Desmond and Ann Heathwood MGH Research Scholar.

Author information

M.E.T., D.R.F., E.E.D., N.K., P.J., N.D.S. and H. Brand designed the study. N.D.S., L.P., K.A.W., M.N., S.P., T.K., D.L., A. Silva, S.J., J.C.S., M.F.L., S.S.S., N.P., J.R.L., N.F., A.V., A.R., K. Steindl, I.S., D.S., N.O., C.J., J.T., S.C., L.A.S., B.B., C. Cesaretti, J.E.G.-O., T.P.B., O.P.S., J.D.H., W.M., K.W.R., B.L.L., M.S., A.M.K., C.-H.C., C.C.M., V.v.H., R.B., J.E.H., S.B.S., K.Y., J.M.G., A.E.L., W.F.C. and D.R.F. recruited patients and collected clinical information and samples. Z.A.K., H. Bengani, L.P., S.E., T.I.J., J.R.W., J.R., A. Stortchevoi, C.M.S., Y.A., B.B.C., M.A., R.R.M., J.K.R., M.Z., J.W.J., E.C.L., S.A.M., N.K., P.L.J., E.E.D., D.R.F. and D.S.D. performed molecular genetics and animal modeling studies. H. Brand, K. Samocha, R.L.C., C. Chiang, A.L., M.L., J.F.G., D.G.M. and M.E.T. performed genomic analyses. J.A.M. performed protein modeling. N.D.S., H. Brand, N.K., J.F.G., P.L.J., E.E.D., D.R.F. and M.E.T. wrote the manuscript, which was revised and approved by all authors.

Correspondence to Erica E Davis or David R FitzPatrick or Michael E Talkowski.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 (PDF 5639 kb)

Supplementary Table 1

Arhina cohort-wide phenotype information. (XLSX 16 kb)

Supplementary Table 2

Individual level phenotype information. (XLSX 22 kb)

Supplementary Table 3

Ethnic specific analysis of SMCHD1 mutation frequency. (XLSX 9 kb)

Supplementary Table 4

DNA methylation analysis of D4Z4 repeats in arhinia cases and familial controls. (XLSX 17 kb)

Supplementary Table 5

Representative zebrafish morphometric data. (XLSX 21 kb)

Supplementary Table 6

Mouse CRISPR of SMCHD1 missense mutations. (XLSX 11 kb)

Supplementary Table 7

Allele-specific expression of SMCHD1 in subjects with a mutation. (XLSX 10 kb)

Supplementary Table 8

Differential expression analysis between arhinia cases and familial controls. (XLSX 1601 kb)

Supplementary Table 9

Enrichment of nominal human genes (P < 0.05) against mouse Smchd1 targets and differentially expressed genes in Smchd1-null mouse. (XLSX 10 kb)

Supplementary Table 10

Overlapping genes with significant dysregulation in the same direction in mouse and human. (XLSX 10 kb)

Supplementary Table 11

Primers used in study. (XLSX 11 kb)

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