SIX6 gene


Gene (OMIM No.)
Function of gene/protein
  • Protein: SIX homeobox 6
  • Regulates other genes by binding to specific DNA regions (transcription factor)
  • Important for initiation of eye development
Clinical phenotype
(OMIM phenotype no.)
  • Optic disc anomalies with retinal and/or macular dystrophy (#212550)
  • Autosomal recessive
Ocular features
Systemic features
  • Midline defects (absence of optic chiasm, optic tracts, geniculate bodies and pituitary glands) have been reported in patients with chromosomal deletions involving SIX6
  • Pituitary abnormalities have been replicated in an animal model
Key investigations
  • B-scan USS to measure axial length to document microphthalmia
  • Electrophysiology
  • OCT and FAF
  • 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 input may be needed due to early onset visual loss
Therapies under research
  • None at present
Further information

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  1.  Aldahmesh MA, Khan AO, Hijazi H, Alkuraya FS. Homozygous truncation of SIX6 causes complex microphthalmia in humans. Clin Genet. 2013;84(2):198‐199
  2.  Boucher CA, Winchester CL, Hamilton GM, Winter AD, Johnson KJ, Bailey ME. Structure, mapping and expression of the human gene encoding the homeodomain protein, SIX2. Gene. 2000;247(1-2):145‐151
  3.  Yariz KO, Sakalar YB, Jin X, et al. A homozygous SIX6 mutation is associated with optic disc anomalies and macular atrophy and reduces retinal ganglion cell differentiation. Clin Genet. 2015;87(2):192‐195
  4.  Bennett CP, Betts DR, Seller MJ. Deletion 14q (q22q23) associated with anophthalmia, absent pituitary, and other abnormalities. J Med Genet. 1991;28(4):280-281
  5.  Gallardo ME, Rodríguez De Córdoba S, Schneider AS, Dwyer MA, Ayuso C, Bovolenta P. Analysis of the developmental SIX6 homeobox gene in patients with anophthalmia/microphthalmia. Am J Med Genet A. 2004;129A(1):92-94
  6.  Ahmad ME, Dada R, Dada T, Kucheria K. 14q(22) deletion in a familial case of anophthalmia with polydactyly. Am J Med Genet A. 2003;120A(1):117-122
  7.  Li X, Perissi V, Liu F, Rose DW, Rosenfeld MG. Tissue-specific regulation of retinal and pituitary precursor cell proliferation. Science. 2002;297(5584):1180-1183

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Updated on November 30, 2020
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