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

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.