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

Table 1 Common chromosomal abnormalities associated with anophthalmia and microphthalmia

Type of chromosomal abnormality	Chromosome abnormality	Other features
Aneuploidy	Trisomy 9 mosaicism	Joint contractures, congenital heart defects, prenatal growth deficiency, learning difficulties, micrognathia, kyphoscoliosis
	Trisomy 13 (patau syndrome)	Holoprosencephaly, moderate microcephaly, coloboma, retinal dysplasia, cyclopia, cleft lip/palate, cardiac defects, genital abnormalities, 86% die within one year
	Trisomy 18 (edwards syndrome)	Polyhydramnios, single umbilical artery, small placenta, low fetal activity, learning difficulties, hypertonicity, hypoplasia of skeletal muscle, subcutaneous, adipose tissue, prominent occiput, low-set malformed auricles, micrognathia, cardiac defects
Triploidy	Triploidy	Large placenta with hydatidiform changes, growth deficiency, syndactyly, congenital heart defects, brain anomalies/holoprosencephaly
Deletion	4p (wolf-hirschhorn syndrome)	Growth deficiency, microcephaly, ocular hypertelorism, cranial asymmetry, learning difficulties, epilepsy, cleft lip/palate, anterior segment dysgenesis
	Deletion 7p15.1-p21.1	Cryptophthalmos, cleft lip/palate, choanal atresia
	13q-, ring 13	Microcephaly, learning difficulties, bilateral retinoblastoma, cardiac defects, hypospadias, cryptorchidism
	Deletion 14q22.1-q23.2	Pituitary hypoplasia
	18q	Midface hypoplasia, small stature, learning difficulties, hypotonia, nystagmus, conductive deafness, microcephaly, midface hypoplasia, genital abnormalities
Duplication	3q syndrome (3q21-ter dup)	Learning difficulties, growth deficiency, hypertrichosis, craniosynostosis, cardiac defects, chest deformities, genital abnormalities, umbilical hernia
	4p syndrome	Learning difficulties, epilepsy, growth deficiency, obesity, microcephaly, characteristic faces, genital abnormalities, kyphoscoliosis
	10q syndrome	Ptosis, short palpebral fissures, camptodactyly, learning difficulties, prenatal growth deficiency, microcephaly, heart and kidney malformations

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.

Table 3 Genes linked with microphthalmia (syndromic/non-syndromic) and its associated anomalies (https://hgmd.cf.ac.uk/ac/index.php)

Phenotype	Gene
Microphthalmia, isolated with coloboma 7	ABCB6
Microphthalmia and cataract	ALDH1A3, SHH, RAB3GAP2, FOXC1
Microphthalmia with facial clefting	ALX1
Microphthalmia, renal aplasia, hearing impairment, developmental delay, micropenis and cryptorchidism	ANOS1
Microphthalmia with linear skin defects	ARHGAP6
Craniosynostosis-microphthalmia syndrome	BCOR
Intellectual disability, cortical atrophy, microphthalmia and autism spectrum disorder
Lenz microphthalmia
Microphthalmia and cataracts
Microphthalmia with associated anomalies
Microphthalmia, syndromic 2
Pediatric total cataract with microphthalmia and microcornea
Anophthalmia, microphthalmia with sclerocornea and hydrocephalus	BMP4
Bilateral microphthalmia and unilateral cataract
Colobomatous microphthalmia	BRPF1, PUF60, TGFB2
Microphthalmia, syndromic	C12orf57, RAB3GAP2, TBC1D32, SCLT1, BCOR, KMT2D, NAA10, LAMB2, SLC18A2
Microphthalmia, colobomatous	C12orf57, SHH
Bilateral microphthalmia with accompanying malformations	CACNA1F, OSGEPL1, COL4A1, GAS2L2, IGFALS, LRP11, MAN1A1, CBR4, PKHD1L1, PRKG2, PDE6B, SUMF1, TBCE
Microphthalmia and/or coloboma	CAPN15
A/M	CHD7, OTX2, STRA6, PUF60, SIX6
Unilateral microphthalmia, isolated	CHD7, wnk4tv2 (isoform of WNK4), abcb9tv2 (isoform of ABCB9), wnk1tv2 (isoform of WNK1), FERMT1, CD22, MYO9B, ccn4tv3, EPB41, INTS11, IARS2RC3H1, ccn4tv3 (isoform of CCN4), EPB41, INTS11, IARS2RC3H1, AGRN, KRT31, PSME3IP, TUBGCP3, XKR4, MYCBP2, ABCC9, RPGRIP1L, MYH11, BHLHE22, ST18, FGF20, GRM8, ABCA13, CAPN11, NHLRC1, GRM6, MEGF10, PALLD, KMT2A, TYR, MFSD13A, HECTD2, MSRB2, ABCA1, KIFC2, FMNL2, ZP4, FRAS1, LIPH, MCCC1, P2RY14, CACNA2D3, SCN11A, GMPPA, PRKAG3, AOX1
Intellectual disability with microphthalmia	CNKSR1
A/M with developmental delay	COL4A1
Cataracts and microphthalmia
Microphthalmia with bilateral microcornea and Peters anomaly
Microphthalmia with linear skin lesions	COX7B, HCCS, NDUFB11
Pediatric perinuclear cataract with microphthalmia	CRYAA
Pediatric total cataract with microphthalmia	CRYBA4
Cataract and microphthalmia	CRYBB1
Cataract and microphthalmia	CRYBB3, BBS2, CRYAA
Nuclear cataracts with microphthalmia	CRYGC
Microphthalmia, fetal vasculature and vitreoretinal dysplasia	CTNNB1
Microphthalmia and agenesis of corpus callosum	DIS3L2
Mandibulofacial dysostosis, type Guion-Almeida, with microphthalmia, coloboma and retinal dystrophy	EFTUD2
Microphthalmia with iris hypoplasia	EPHA2
Colobomatous microphthalmia, ptosis, syndactyly and nephropathy	FAT1
Microphthalmia, coloboma, cardiac anomalies, renal dysfunction and limb malformations
Microphthalmia, and intellectual developmental disorder with dysmorphic facies and behavioral abnormalities	FBXO11
Microphthalmia and choroidal osteoma	FNBP4
Glaucoma, microphthalmia, iris anomalies, dysmorphic facial features, club foot, cognitive impairment and deafness	FOXC1
Bilateral microphthalmia and anterior segment dysgenesis	FOXE3
Microphthalmia with sclerocornea
Microphthalmia, nonsyndromic bilateral
Sclerocornea-microphthalmia-aphakia complex
Microphthalmia and anterior segment developmental anomalies	GDF6
Microphthalmia, congenital cataracts and microcornea	GJA3
Congenital cataract with microcornea, microphthalmia and posterior capsule defect	GJA8
Dystonia, bilateral ptosis, microphthalmia and speech and motor developmental delay	GNAL
Microphthalmia with linear skin lesions and autism spectrum disorder	HCCS
Microphthalmia, syndromic 7
Bilateral microphthalmia, isolated	hlcstv 4 (isoform of HLCS), ATRN, pax6tv32 (isoform of PAX6), TAS1R3, CERS2, NUMA1, TSFM, SLC5A11, PRKAG2, CFTR, GCK, THSD7A, CUZD1, VTI1A, UNC13D, CACNA1G, GFAP, LRP5
Colobomatous microphthalmia syndrome, X-linked	HMGB3
Ocular coloboma, microphthalmia and cataract	IPO13
Microphthalmia and coloboma	KIF17, MAB21L1
Microcephaly, long eyelashes, microphthalmia	KMT2A
Microphthalmia, failure to thrive, skeletal anomalies and neurological disorders
Unilateral microphthalmia with accompanying malformations	KRT23, VPS13D, MYH2, TRIM2, USP38, MYBPC3, KIAA2026, RYR2, MAP3K21, UNC13D, CHD7
Microphthalmia and aniridia	MAB21L1
Microphthalmia	MAB21L1, OTX2, MAB21L2, PRSS56, ALDH1A3, RAX, VSX1, PIEZO2, STRA6, SOX2, CHD7, RARB, DSC3, MFRP, RAB3GAP1, PXDN, GJA8, HMX1, MYO10, OLFM2, EPHA2, BCOR, TENM3, FOXE3, TMX3, VSX2, otx2tv5, CRYBA4, PAX6, VAX1, C12orf57, SEMA3E, RBP4, DHX38, ZNF219, GDF3, SIX6
Bilateral colobomatous microphthalmia, autosomal-dominant	MAB21L2
Microphthalmia/coloboma and skeletal dysplasia syndrome
Syndromic microphthalmia, type 14
Cataract, anterior segment dysgenesis and microphthalmia	MAF
Posterior microphthalmia, non-pigmented retinitis pigmentosa, optic nerve drusen, and retinoschisis	MFRP
Microphthalmia with retinitis pigmentosa	MFRP, PRSS56
Microphthalmia, bilateral	MIP, PAX6
Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism and deafness	mitftv1 (isoform of MITF), MITF
Microphthalmia, bilateral with sclerocornea	NDP
Pediatric cataract with microphthalmia, microcornea and nystagmus	NHS
Pediatric total cataract with microphthalmia, microcornea and nystagmus
Microcephaly, microphthalmia and cataracts	OCLN
Microphthalmia and coloboma	OLFM2, RAX, TMX3, PAX6, SEMA3E, ABCB6, RBP4
Combined pituitary hormone deficiency, bilateral microphthalmia and agenesis of the left internal carotid artery	OTX2
Combined pituitary hormone deficiency, syndromic microphthalmia and retinal dystrophy
Microphthalmia, ectopic pituitary and growth hormone deficiency
Microphthalmia, pituitary abnormalities and intellectual disability
Microphthalmia, type 5
Microphthalmia, syndromic 5	otx2tv5 (isoform of OTX2)
Syndromic microphthalmia
Bilateral microphthalmia, anophthalmia or coloboma	PAX6
Bilateral microphthalmia, congenital cataract and glaucoma
Bilateral microphthalmia, primary aphakia, coloboma and iris hypoplasia
Microphthalmia, cataracts and nystagmus
Microphthalmia, late-onset keratitis and iris coloboma/aniridia
Anterior segment dysgenesis and microphthalmia	PITX3
Congenital cataract and microphthalmia	PITX3, CRYGC
Non-syndromic A/M	PORCN
Microphthalmia with limb anomalies	PORCN, FNBP4, SMOC1
Mental retardation, microphthalmia, choroid coloboma, microcephaly, renal hypoplasia and spastic paraplegia	PQBP1
Microphthalmia and Peters anomaly	PRR12
Unilateral microphthalmia
Unilateral microphthalmia and Peters anomaly
Microphthalmia with corneal opacification	PXDN
Microphthalmia, sclerocornea, Peters anomaly and aphakia
Microphthalmia and anterior segment dysgenesis	PXDN, GJA8, PAX6, CRYGC, CRYAA
Microphthalmia and diaphragmatic hernia	RARB
Microphthalmia and dystonia
Microphthalmia, syndromic 12
Microphthalmia, isolated, with coloboma 10	RBP4
Microphthalmia, anophthalmia and coloboma disease	RERE, CDON, IQGAP1, CASK, MYO10, TENM3, POLR2A, WNT2B, KIF26B, MICU1, RBP4, FIG4, GDF6
Lenz microphthalmia syndrome	SALL1
Microphthalmia, coloboma and optic nerve hypoplasia	SALL4
Microphthalmia and extensive colobomas of the globes	SIX6
Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary, hypercalcemic type	SMARCA4
Bosma arrhinia microphthalmia syndrome	SMCHD1
Alzahrani-Kuwahara syndrome and microphthalmia	SMG8
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
Bilateral microphthalmia, microcornea, learning disability and developmental delay
Microphthalmia syndromic 3
Microphthalmia, developmental delay, hearing loss and dysmorphic features
Microphthalmia, iris coloboma, anal atresia and nasal skin tag
Bilateral microphthalmia	SOX2, PAX6
Microphthalmia, anophthalmia and coloboma
Microphthalmia 3	SOX2, RAX
Mild intellectual disability with microphthalmia, coloboma, hypopituitarism, facial dysmorphology and dental anomalies	SOX3
Microphthalmia, syndromic 9	STRA6
Bilateral microphthalmia, congenital cataract, microcephaly, and global developmental delay	TENM3
Microphthalmia, isolated, with coloboma 9
Syndromic microphthalmia 15
Microphthalmia, congenital cataracts and microcephaly	TUBA1A
Microphthalmia, bilateral and coloboma	VSX2
Microphthalmia, cataract and iris abnormality
Anophthalmia and microphthalmia	VSX2, ALDH1A3, PXDN, FOXE3
Microphthalmia and cataract	VSX2, EPHA2
A/M	VSX2, SOX2, RAX, FOXE3, ALDH1A3
Pulmonary hypoplasia, diaphragmatic anomalies, A/M and cardiac defects syndrome	WNT7B
Microcephaly, Microphthalmia, Hyperpigmentation of the skin, Global developmental delay	XPA
Microphthalmia and bilateral chorioretinal coloboma	YAP1
Microphthalmia and bilateral uveal coloboma
Microphthalmia/coloboma	YAP1, KMT2D

A/M: Anophthalmia and microphthalmia; ABCA1: ATP binding cassette subfamily A member 1; ABCA13: ATP binding cassette subfamily A member 13; ABCB6: ATP binding cassette subfamily B member 6; ABCC9: ATP binding cassette subfamily C member 9; AGRN: Agrin; ALDH1A3: Aldehyde dehydrogenase 1 family member A3; ALX1: Aristaless-like homeobox 1; ANOS1: Anosmin 1; AOX1: Aldehyde oxidase 1; ARHGAP6: Rho GTPase activating protein 6; BBS2: Bardet-biedl syndrome 2; BCOR: BCL6 Corepressor; BMP4: Bone morphogenetic protein 4; BRPF1: Bromodomain and PHD finger containing protein; CACNA1F: Calcium channel voltage-dependent, alpha-1F subunit; CACNA2D3: Calcium channel voltage-dependent alpha 2/delta subunit 3; CAPN11: Calpain 11; CAPN15: Calpain 15; CBR4: Carbonyl reductase 4; CD22: CD22 Antigen; CHD7: Chromodomain helicase DNA binding protein 7; CNKSR1: Connector enhancer of kinase suppressor of Ras 1; COL4A1: Collagen type IV alpha 1; COX7B: Cytochrome c oxidase subunit 7B; CRYAA: Crystallin alpha A; CRYBA4: Crystallin beta A4; CRYBB1: Crystallin beta B1; CRYBB3: Crystallin beta B3; CRYGC: Crystallin gamma C; CTNNB1: Catenin beta 1; C12orf57: Chromosome 12 open reading frame 57; DIS3L2: DIS3 like 3'-5' exoribonuclease 2; EFTUD2: Elongation factor Tu GTP binding domain containing 2; EPB41: Erythrocyte membrane protein band 4.1; EPHA2: EPH receptor A2; FAT1: FAT atypical cadherin 1; FERMT1: FERM doamin-containing kindlin 1; FGF20: Fibroblast growth factor 20; FMNL2: Formin like 2; FOXC1: Forkhead box C1; FOXE3: Forkhead box E3; FRAS1: Fraser extracellular matrix complex subunit 1; GAS2L2: Growth arrest-specific 2 like 2; GDF6: Growth/differentiation factor 6; GJA3: Gap junction protein alpha 3; GJA8: Gap junction protein alpha 8; GMPPA: GDP-mannose pyrophosphorylase A; GNAL: G protein subunit alpha L; GRM6: Glutamate receptor metabotropic 6; GRM8: Glutamate receptor metabotropic 8; HCCS: Holocytochrome C Synthase; HECTD2: HECT domain E3 ubiquitin protein ligase 2; KIFC2: Kinesin family member C2; IARS2: Isoleucyl-tRNA synthetase 2; IGFALS: Insulin-like growth factor binding protein, acid-labile subunit; INTS11: Integrator complex subunit 11; IPO13: Importin 13; KIF17: Kinesin family member 17; KMT2A: Lysine-specific methyltransferase 2A; KMT2D: Lysine-specific methyltransferase 2D; KRT31: Keratin 31; LAMB2: Laminin beta 2; LIPH: Lipase H; LRP11: LDL receptor related protein 11; MAB21L1: Mab-21 like 1; MAB21L2: Mab-21 like 2; MAN1A1: Mannosidase alpha class 1A member 1; MCCC1: Methylcrotonoyl-CoA carboxylase 1; MEGF10: Multiple EGF like domains 10; MFSD13A: Major facilitator superfamily domain containing protein 13A; MITF: Microphthalmia associated transcription factor; MSRB2: Methionine sulfoxide reductase B2; MYCBP2: Myc binding protein 2. MYH11: Myosin heavy chain 11; MYO9B: Myosin IXB; NAA10: N-Alpha acetyltransferase 10, NatA catalytic subunit; NDP: Norrin cystine knot growth factor NDP; NDUFB11: NADH-ubiquinone oxidoreductase 1 beta subcomplex 11; NHLRC1: NHL repeat containing protein 1; NHS: NHS actin remodeling regulator; OSGEPL1: O-sialoglycoprotein endopeptidase-like 1; OTX2: Orthodenticle homeobox 2; PALLD: Palladin; PAX6: Paired box 6; PDE6B: Phosphodiesterase 6B; PKHD1L1: PKHD1-like 1; PORCN: Porcupine O-acyltransferase; PRKAG3: Protein kinase AMP-activated non-catalytic gamma 3; PRKG2: Protein kinase cGMP-dependent type II; PUF60: Poly(U) binding splicing factor 60-KD; PXDN: Peroxidasin; P2RY14: Purinergic receptor P2Y, G protein-coupled 14; RAB3GAP2: RAB3 GTPase activating protein non-catalytic subunit; RARB: Retinoic acid receptor beta; RBP4: Retinol binding protein 4; RPGRIP1L: RPGR interacting protein 1 like; SCLT1: Sodium channel and clathrin linker 1; SCN11A: Sodium voltage-gated channel alpha subunit 11; SHH: Sonic hedgehog; SIX6: SIX homeobox 6; SLC18A2: Solute carrier family 18 (vesicular monoamine) member 2; SOX2: SRY-box 2; STRA6: Stimulated by retinoic acid 6; SUMF1: Sulfatase modifying factor 1; TBC1D32: TBC1 domain family member 32; TBCE: Tubulin-specific chaperone E; TENM3: Teneurin transmembrane protein 3; TGFB2: Transforming growth factor beta 2; TUBGCP3: Tubulin gamma complex associated protein 3; TYR: Tyrosinase; VSX2: Visual system homeobox 2; WNT7B: Wnt family member 7B; XKR4: XK-related protein 4; YAP1: Yes1 associated transcriptional regulator; ZP4: Zona pellucida glycoprotein 4.