Genetic and environmental factors contributing to anophthalmia and microphthalmia: Current understanding and future directions

Table 2 Genes associated with Anophthalmia (syndromic/non-syndromic) and its associated anomalies (https://hgmd.cf.ac.uk/ac/index.php)

Phenotype	Gene
Anophthalmia	ALDH1A3, MFRP, SOX2, RAX, OTX2, FRAS1, BMP4
Unilateral anophthalmia, isolated	ARG1
Anophthalmia and kidney abnormalities	BCOR
Anophthalmia and blepharophimosis	BMP4
A/M	CHD7, OTX2, STRA6, PUF60, SIX6
A/M with developmental delay	COL4A1
Developmental delay with anophthalmia	EPHA6
Anophthalmia and skeletal anomalies	GDF3
Anophthalmia, bilateral	GDF6, VSX2, OTX2
Holoprosencephaly with anophthalmia, branchial arch anomalies and central nervous system anomalies	GLI2
Bilateral anophthalmia, intellectual disability and rhizomelic skeletal dysplasia	MAB21L2
Waardenburg anophthalmia syndrome 4	MITF
Anophthalmia and isolated growth hormone deficiency	OTX2
Anophthalmia with corpus callosum hypoplasia, pituitary gland hypoplasia and vermian hypoplasia
Anophthalmia, growth delays, intellectual disability, and autism
Anophthalmia, hearing impairment, dysmorphic facial features and abnormal pituitary development causing growth failure
Anophthalmia, pituitary hypoplasia and ear anomalies
Bilateral anophthalmia, syndromic
Hypopituitarism with anophthalmia, dysmorphic facies, developmental delay and patent ductus arteriosus
Bilateral microphthalmia, anophthalmia or coloboma	PAX6
Non-syndromic A/M	PORCN
Brain malformations, anophthalmia, hepatomegaly, bile duct atresia and Müllerian duct agenesis	ptk7ie (isoform of PTK7)
Anophthalmia and sclerocornea	RAX
Anophthalmia, hypopituitarism, diabetes insipidus, bilateral cleft lip and palate
Microphthalmia, anophthalmia and coloboma disease	RERE, CDON, IQGAP1, CASK, MYO10, TENM3, POLR2A, WNT2B, KIF26B, MICU1, RBP4, FIG4, GDF6
Waardenburg anophthalmia syndrome	SMOC1
A/M, developmental delay, short stature and ataxic gait	SOX2
A/M, mental retardation, short stature and ataxic gait
A/M, mental retardation, short stature and unsteady gait
Anophthalmia and facial dysmorphism
Anophthalmia syndrome and dental anomalies
Anophthalmia with status dystonicus	SOX2
Anophthalmia-esophageal-genital syndrome
Anophthalmia, facial dysmorphism, delayed psychomotor development and language acquisition
Anophthalmia, global developmental delay, hypotonia, delayed language development and delayed gross motor development
Anophthalmia, hearing loss and brain abnormalities
Anophthalmia, hypogonadotropic hypogonadism and growth hormone deficiency
Bilateral anophthalmia and sensorineural hearing loss
Sox2 anophthalmia syndrome
Bilateral anophthalmia	SOX2, GJA8
Microphthalmia, anophthalmia and coloboma	SOX2, PAX6
Anophthalmia and diaphragmatic defects	STRA6
Anophthalmia syndrome
Colobomatous microanophthalmia	STRA6, TENM3
Anophthalmia and microphthalmia	VSX2, ALDH1A3, PXDN, FOXE3
A/M	VSX2, SOX2, RAX, FOXE3, ALDH1A3
Unilateral anophthalmia with accompanying malformations	WASHC5
Pulmonary hypoplasia, diaphragmatic anomalies, A/M and cardiac defects syndrome	WNT7B

A/M: Anophthalmia and microphthalmia; ALDH1A3: Aldehyde dehydrogenase 1 family member A3; ARG1: Arginase 1; BCOR: BCL6 corepressor; BMP4: Bone morphogenetic protein 4; CASK: Calcium/calmodulin dependent serine protein kinase; CDON: Cell adhesion molecule-related/downregulated by oncogenes; CHD7: Chromodomain helicase DNA binding protein 7; COL4A1: Collagen type IV alpha 1; EPHA6: Ephrin receptor ephA6; FIG4: FIG4 phosphoinositide 5-phosphatase; FOXE3: Forkhead box E3; FRAS1: Fraser extracellular matrix complex subunit 1; GDF3: Growth/differentiation factor 3; GDF6: Growth/differentiation factor 6; GJA8: Gap junction protein alpha 8; GLI2: GLI-kruppel family member 2; IQGAP1: IQ motif containing GTPase activating protein 1; KIF26B: Kinesin family member 26B; MAB21L2: Mab-21 like 2; MICU1: Mitochondrial calcium uptake protein 1; MITF: Microphthalmia associated transcription factor; MFRP: Membrane-type frizzled-related protein; MYO10: Myosin X; OTX2: Orthodenticle homeobox 2; PAX6: Paired box gene 6; POLR2A: Polymerase II, RNA, subunit A; PORCN: Porcupine O-acyltransferase; PTK7: Protein tyrosine kinase 7; PUF60: Poly(U) binding splicing factor 60-KD; PXDN: Peroxidasin; RAX: Retina and anterior neural fold homeobox; RBP4: Retinol binding protein 4; RERE: Arginine-glutamic acid dipeptide repeats; SIX6: SIX homeobox 6; SMOC1: SPARC related modular calcium binding 1; SOX2: SRY-box 2; STRA6: Stimulated by retinoic acid 6; TENM3: Teneurin transmembrane protein 3; VSX2: Visual system homeobox 2; WASHC5: WASH complex subunit5;WNT2B: Wnt family member 2B; WNT7B: Wnt family member 7B.