Eye Development Genes and Known Syndromes

Overview

Journal Mol Genet Metab

Specialty Endocrinology

Date 2011 Oct 19

PMID 22005280

Citations 53

Authors

Anne M Slavotinek

Affiliations

Soon will be listed here.

Abstract

Anophthalmia and microphthalmia (A/M) are significant eye defects because they can have profound effects on visual acuity. A/M is associated with non-ocular abnormalities in an estimated 33-95% of cases and around 25% of patients have an underlying genetic syndrome that is diagnosable. Syndrome recognition is important for targeted molecular genetic testing, prognosis and for counseling regarding recurrence risks. This review provides clinical and molecular information for several of the commonest syndromes associated with A/M: Anophthalmia-Esophageal-Genital syndrome, caused by SOX2 mutations, Anophthalmia and pituitary abnormalities caused by OTX2 mutations, Matthew-Wood syndrome caused by STRA6 mutations, oculofaciocardiodental syndrome and Lenz microphthalmia caused by BCOR mutations, Microphthalmia Linear Skin pigmentation syndrome caused by HCCS mutations, Anophthalmia, pituitary abnormalities, polysyndactyly caused by BMP4 mutations and Waardenburg anophthalmia caused by mutations in SMOC1. In addition, we briefly discuss the ocular and extraocular phenotypes associated with several other important eye developmental genes, including GDF6, VSX2, RAX, SHH, SIX6 and PAX6.

Citing Articles

Decoding Facial Dissymmetry: A Comparative Morphological Study on Human Skulls and Facial Structures.

Divaris M Plast Reconstr Surg Glob Open. 2025; 13(2):e6514.

PMID: 39974771 PMC: 11838159. DOI: 10.1097/GOX.0000000000006514.

Deciphering the dynamic single-cell transcriptional landscape in the ocular surface ectoderm differentiation system.

Zhang C, Lin Z, Yu Y, Wu S, Huang H, Huang Y Life Med. 2025; 3(5):lnae033.

PMID: 39872440 PMC: 11749776. DOI: 10.1093/lifemedi/lnae033.

Bibliometric analysis of microphthalmos and anophthalmos over 20 years: from 2004 to 2023.

Wang M, Li G, Zhang J Int J Ophthalmol. 2024; 17(11):2120-2128.

PMID: 39559321 PMC: 11528269. DOI: 10.18240/ijo.2024.11.19.

A Case of Congenital Bilateral Anophthalmia.

Alhubaishi F, Almedfaa A, Andacheh M Curr Health Sci J. 2024; 50(2):328-331.

PMID: 39371063 PMC: 11447493. DOI: 10.12865/CHSJ.50.02.20.

Molecular mechanisms controlling vertebrate retinal patterning, neurogenesis, and cell fate specification.

Zhang X, Leavey P, Appel H, Makrides N, Blackshaw S Trends Genet. 2023; 39(10):736-757.

PMID: 37423870 PMC: 10529299. DOI: 10.1016/j.tig.2023.06.002.

References

Simeone A, Acampora D, Mallamaci A, Stornaiuolo A, DApice M, Nigro V . A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J. 1993; 12(7):2735-47. PMC: 413524. DOI: 10.1002/j.1460-2075.1993.tb05935.x. View

Bakrania P, Robinson D, Bunyan D, Salt A, Martin A, Crolla J . SOX2 anophthalmia syndrome: 12 new cases demonstrating broader phenotype and high frequency of large gene deletions. Br J Ophthalmol. 2007; 91(11):1471-6. PMC: 2095460. DOI: 10.1136/bjo.2007.117929. View

Abouzeid H, Youssef M, ElShakankiri N, Hauser P, Munier F, Schorderet D . PAX6 aniridia and interhemispheric brain anomalies. Mol Vis. 2009; 15:2074-83. PMC: 2765237. View

Fantes J, Ragge N, Lynch S, McGill N, Collin J, Howard-Peebles P . Mutations in SOX2 cause anophthalmia. Nat Genet. 2003; 33(4):461-3. DOI: 10.1038/ng1120. View

Schneider A, Bardakjian T, Reis L, Tyler R, Semina E . Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia. Am J Med Genet A. 2009; 149A(12):2706-15. PMC: 2787970. DOI: 10.1002/ajmg.a.33098. View

Zenteno J, Perez-Cano H, Aguinaga M . Anophthalmia-esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes. Am J Med Genet A. 2006; 140(18):1899-903. DOI: 10.1002/ajmg.a.31384. View

Reis L, Tyler R, Schneider A, Bardakjian T, Semina E . Examination of SOX2 in variable ocular conditions identifies a recurrent deletion in microphthalmia and lack of mutations in other phenotypes. Mol Vis. 2010; 16:768-73. PMC: 2862242. View

Dateki S, Kosaka K, Hasegawa K, Tanaka H, Azuma N, Yokoya S . Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype. J Clin Endocrinol Metab. 2009; 95(2):756-64. DOI: 10.1210/jc.2009-1334. View

Wimplinger I, Shaw G, Kutsche K . HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations?. Mol Vis. 2007; 13:1475-82. View

10.

Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt A, Ragge N, Dateki S, Fukami M . A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency. Hum Genet. 2010; 127(6):721-9. DOI: 10.1007/s00439-010-0820-9. View

11.

Taranova O, Magness S, Fagan B, Wu Y, Surzenko N, Hutton S . SOX2 is a dose-dependent regulator of retinal neural progenitor competence. Genes Dev. 2006; 20(9):1187-202. PMC: 1472477. DOI: 10.1101/gad.1407906. View

12.

Bakrania P, Ugur Iseri S, Wyatt A, Bunyan D, Lam W, Salt A . Sonic hedgehog mutations are an uncommon cause of developmental eye anomalies. Am J Med Genet A. 2010; 152A(5):1310-3. DOI: 10.1002/ajmg.a.33239. View

13.

Hayashi S, Okamoto N, Makita Y, Hata A, Imoto I, Inazawa J . Heterozygous deletion at 14q22.1-q22.3 including the BMP4 gene in a patient with psychomotor retardation, congenital corneal opacity and feet polysyndactyly. Am J Med Genet A. 2008; 146A(22):2905-10. DOI: 10.1002/ajmg.a.32519. View

14.

Ugur Iseri S, Wyatt A, Nurnberg G, Kluck C, Nurnberg P, Holder G . Use of genome-wide SNP homozygosity mapping in small pedigrees to identify new mutations in VSX2 causing recessive microphthalmia and a semidominant inner retinal dystrophy. Hum Genet. 2010; 128(1):51-60. DOI: 10.1007/s00439-010-0823-6. View

15.

Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S, Collins J . Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest. 2006; 116(9):2442-55. PMC: 1551933. DOI: 10.1172/JCI28658. View

16.

Kamachi Y, Uchikawa M, Kondoh H . Pairing SOX off: with partners in the regulation of embryonic development. Trends Genet. 2000; 16(4):182-7. DOI: 10.1016/s0168-9525(99)01955-1. View

17.

Rainger J, van Beusekom E, Ramsay J, McKie L, Al-Gazali L, Pallotta R . Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans and mice. PLoS Genet. 2011; 7(7):e1002114. PMC: 3131273. DOI: 10.1371/journal.pgen.1002114. View

18.

Hanel M, Hensey C . Eye and neural defects associated with loss of GDF6. BMC Dev Biol. 2006; 6:43. PMC: 1609107. DOI: 10.1186/1471-213X-6-43. View

19.

Bird L, Krous H, Eichenfield L, Swalwell C, Jones M . Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): a clue to the pathogenesis of oncocytic cardiomyopathy?. Am J Med Genet. 1994; 53(2):141-8. DOI: 10.1002/ajmg.1320530205. View

20.

Stark Z, Storen R, Bennetts B, Savarirayan R, Jamieson R . Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring. Eur J Hum Genet. 2011; 19(7):753-6. PMC: 3137491. DOI: 10.1038/ejhg.2011.11. View