SMCHD1 gene


Gene (OMIM No.)
Function of gene/protein
  • Protein: structural maintenance of chromosomes flexible hinge domain containing protein 1
  • Regulates the activity of genes by altering DNA structure (adding methyl groups to silence genes)
  • Important for X-inactivation (one X chromosome in females is permenantly inactivated early in embryonic development)
  • SMCHD1 protein is crucial for the development of eyes, nose and other craniofacial structures
  • Also inactivates DUX4, which is thought to control the activity of other genes
Clinical phenotype
(OMIM phenotype no.)
  • Bosma arhinia microphthalmia syndrome (#603457)
  • Fascioscapulohumeral muscular dystrophy 2, digenic (#158901)
  • Autosomal dominant
Ocular features
Systemic featuresBosma arhinia microphthalmia syndrome:
  • Complete arhinia
  • Anosmia (MRI shows no olfactory structures)
  • Craniofacial (chonal atresia, absent paranasal sinuses, hypoplastic maxilla, high-arched/cleft palate)
  • Hypogonadotropic hypogonadism (cryptorchidism, micropenis, anomalies of menarche in females)
  • Normal cognition
Key investigations
  • B-scan USS to measure axial length to document microphthalmia
  • Electrophysiology
  • MRI brain and orbit
  • Systemic assessment with a paediatrician and other relevant specialists
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (MAC)
  • Whole genome sequencing
  • Multidisciplinary approach
Therapies under research
  • None at present
Further information

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Additional information

It has been suggested by Shaw et al that pathogenic variants in SMCHD1 is not fully penetrant, resulting in marked intra- and interfamilial phenotypic variability.

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  1.  Blewitt ME, Gendrel AV, Pang Z, et al. SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nat Genet. 2008;40(5):663‐669
  2.  Graham JM Jr, Lee J. Bosma arhinia microphthalmia syndrome. Am J Med Genet A. 2006;140(2):189‐193
  3.  Lemmers RJ, Tawil R, Petek LM, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012;44(12):1370‐1374
  4.  Shaw ND, Brand H, Kupchinsky ZA, et al. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome [published correction appears in Nat Genet. 2017 May 26;49(6):969]. Nat Genet. 2017;49(2):238-248

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Updated on November 30, 2020
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