Anophthalmia is defined as a complete absence of one eye or both the eyes, while microphthalmia represents the presence of a small eye within the orbit. The estimated birth prevalence for anophthalmia is approximately 3 per 100000 live births, and for microphthalmia, it is around 14 per 100000 live births. However, combined evidence suggests that the prevalence of these malformations could be as high as 30 per 100000 individuals. Microphthalmia is reported to occur in 3.2% to 11.2% of blind children. Anophthalmia and microphthalmia (A/M) are part of a phenotypic spectrum alongside ocular coloboma, hypothesized to share a common genetic basis. Both A/M can occur in isolation or as part of a syndrome. Their complex etiology involves chromosomal aberrations, monogenic inheritance pattern, and the contribution of environmental factors such as gestational-acquired infections, maternal vitamin A deficiency (VAD), exposure to X-rays, solvent misuse, and thalidomide exposure. A/M exhibit significant clinical and genetic heterogeneity with over 90 genes identified so far. Familial cases of A/M have a complex genetic basis, including all Mendelian modes of inheritance, i.e., autosomal dominant, recessive, and X-linked. Most cases arise sporadically due to de novo mutations. Examining gene expression during eye development and the effects of various environmental variables will help us better understand the phenotypic heterogeneity found in A/M, leading to more effective diagnosis and management strategies. The present review focuses on key genetic factors, developmental abnormalities, and environmental modifiers linked with A/M. It also emphasizes at potential research areas including multiomic methods and disease modeling with induced pluripotent stem cell technologies, which aim to create innovative treatment options.

• Anophthalmia
• Microphthalmia
• Eye development
• SRY-Box 2
• Orthodenticle homeobox 2

• coloboma
• microphthalmia
• orbital cyst

To determine the causes of severe visual impairment and blindness in children in schools for the blind in Maharashtra, India.

Children aged <16 years, enrolled in the schools for the blind in Maharashtra state, India were examined between October 2018 and December 2019. The anatomical sites and etiology for blindness were recorded using the World Health Organization’s standard reporting form. Causes of blindness were compared among different regions of the state and also by different age groups.

Of the 1,969 students examined from 39 schools for the blind, 188 children (9.5%) had severe visual impairment and 1,666 children (84.6%) were blind. Whole globe anomalies (794, 42.8%) were the most common anatomical site of vision loss in children, followed by corneal (289, 15.6%) and retinal abnormalities (280, 15.2%). Corneal causes were second most common in the poorer districts of Vidarbha (15.3%) and Marathwada (14.6%), whereas retinal causes were second most common in the wealthier regions of western Maharashtra (18.3%) and Khandesh (24.1%). Nearly one-third (593, 32%) of children were blind from potentially avoidable causes. Preventable blindness consisting of corneal causes and retinopathy of prematurity was seen in 281 (15.2%) cases, whereas treatable causes comprising of lens-related causes, glaucomas, refractive errors, amblyopia, and uveitis accounted for another 311 (16.8%). Among the younger children (≤10 years), the proportion of corneal blindness was lower (83/623, 13.3% vs. 206/1232, 16.7%) and that of retinal blindness was higher (119/623, 19% vs. 163/1232, 13.2%) than the older children.

Whole globe anomalies constitute a major cause of SVI and blindness in Maharashtra. There seems to be an increase in the proportion of retinal blindness, especially retinopathy of prematurity, suggesting a need for increased screening coverage.

• Childhood blindness
• India
• Maharashtra
• schools for blind
• visual impairment

• Anophthalmia
• Coloboma
• Developmental Eye Defects
• Environmental Causes
• Microphthalmia
• Ocular Teratogens
• Uveal Coloboma

• congenital disorders
• disability
• global health
• ophthalmology

• Child
• Coloboma/complications
• Coloboma/surgery
• Cysts/complications
• Cysts/surgery
• Developing Countries
• Eye
• Female
• Health Services Accessibility
• Humans
• Microphthalmos/complications

• congenital cataract
• congenital ocular malformations
• microphthalmia
• persistent pupillary membrane

• Choroid
• Embryology and development
• Eye (Globe)
• Iris
• Retina

• Adolescent
• Anophthalmos/diagnosis
• Anophthalmos/epidemiology
• Anophthalmos/physiopathology
• Blindness/diagnosis
• Blindness/epidemiology
• Blindness/physiopathology
• Cataract/diagnosis
• Cataract/epidemiology
• Cataract/physiopathology
• Child
• Child, Preschool
• Coloboma/diagnosis
• Coloboma/epidemiology
• Coloboma/physiopathology
• Cornea/abnormalities
• Cross-Sectional Studies
• Female
• Humans
• India/epidemiology
• Infant
• Infant, Newborn
• Male
• Microphthalmos/diagnosis
• Microphthalmos/epidemiology
• Microphthalmos/physiopathology
• Nystagmus, Pathologic/diagnosis
• Nystagmus, Pathologic/epidemiology
• Nystagmus, Pathologic/physiopathology
• Retinal Detachment/diagnosis
• Retinal Detachment/epidemiology
• Retinal Detachment/physiopathology
• Retrospective Studies
• Strabismus/diagnosis
• Strabismus/epidemiology
• Strabismus/physiopathology
• Syndrome
• Visual Acuity/physiology

• Antisynthetase syndrome
• anti-Ro antibodies
• inflammatory myopathy
• pregnancy

• Blind students
• cataract
• glaucoma
• low-vision aid
• refractive error
• retinopathy of prematurity

Maternally skewed transmission of traits has been associated with genomic imprinting and oocyte-derived mRNA. We report canine congenital eye malformations, caused by an amino acid deletion (K12del) near the N terminus of retinol-binding protein (RBP4). The disease is only expressed when both dam and offspring are deletion homozygotes. RBP carries vitamin A (retinol) from hepatic stores to peripheral tissues, including the placenta and developing eye, where it is required to synthesize retinoic acid. Gestational vitamin A deficiency is a known risk factor for ocular birth defects. The K12del mutation disrupts RBP folding in vivo, decreasing its secretion from hepatocytes to serum. The maternal penetrance effect arises from an impairment in the sequential transfer of retinol across the placenta, via RBP encoded by maternal and fetal genomes. Our results demonstrate a mode of recessive maternal inheritance, with a physiological basis, and they extend previous observations on dominant-negative RBP4 alleles in humans.

• RBP4
• canine genetics
• congenital eye defect
• genome-wide association study
• maternal inheritance
• microphthalmia
• nuclear magnetic resonance
• vitamin A
• western blotting
• whole genome sequencing

• Amino Acid Sequence
• Animals
• Base Pairing/genetics
• Dogs/genetics
• Eye Diseases/blood
• Eye Diseases/congenital
• Eye Diseases/genetics
• Eye Diseases/veterinary
• Female
• Genes, Recessive
• Genetic Loci
• Genotype
• HeLa Cells
• Humans
• Male
• Maternal Inheritance/genetics
• Microphthalmos/blood
• Microphthalmos/genetics
• Pedigree
• Phenotype
• Prealbumin/metabolism
• Protein Folding
• Retinol-Binding Proteins, Plasma/chemistry
• Retinol-Binding Proteins, Plasma/genetics
• Sequence Deletion
• Vitamin A/blood

• R01 EY019497 NEI NIH HHS

• ALDH1A3 gene
• Autosomal recessive anophthalmia and microphthalmia
• Consanguineous families
• Exome sequencing
• Mutations
• Variants

• Coloboma
• Colobomos
• Congenital eye malformation
• Eye development
• Optic fissure

Ocular coloboma is a common eye malformation arising from incomplete closure of the human optic fissure during development. Multiple genetic mutations contribute to the disease process, showing extensive genetic heterogeneity and complexity of coloboma spectrum diseases. In this study, we aimed to unravel the genetic cause of a consanguineous family with unilateral coloboma and retinoschisis. The subjects were recruited and underwent specialized ophthalmologic clinical examination. A combination of whole exome sequencing (WES), homozygosity mapping, and comprehensive variant analyses was performed to uncover the causative mutation. Only one homozygous mutation (c.113 T > C, p.I38T) in RAX gene survived our strict variant filtering process, consistent with an autosomal recessive inheritance pattern. This mutation segregated perfectly in the family and is located in a highly conserved functional domain. Crystal structure modeling indicated that I38T affected the protein structure. We describe a patient from a consanguineous Chinese family with unusual coloboma, proven to harbor a novel RAX mutation (c.113 T > C, p.I38T, homozygous), expanding the phenotypic variability of ocular coloboma and RAX mutations.

• ALDH1A3
• Anophthalmia
• Eye development
• Incomplete penetrance
• Microphthalmia

Ocular coloboma is a congenital defect resulting from failure of normal closure of the optic fissure during embryonic eye development. This birth defect causes childhood blindness worldwide, yet the genetic etiology is poorly understood. Here, we identified a novel homozygous mutation in the SALL2 gene in members of a consanguineous family affected with non-syndromic ocular coloboma variably affecting the iris and retina. This mutation, c.85G>T, introduces a premature termination codon (p.Glu29*) predicted to truncate the SALL2 protein so that it lacks three clusters of zinc-finger motifs that are essential for DNA-binding activity. This discovery identifies SALL2 as the third member of the Drosophila homeotic Spalt-like family of developmental transcription factor genes implicated in human disease. SALL2 is expressed in the developing human retina at the time of, and subsequent to, optic fissure closure. Analysis of Sall2-deficient mouse embryos revealed delayed apposition of the optic fissure margins and the persistence of an anterior retinal coloboma phenotype after birth. Sall2-deficient embryos displayed correct posterior closure toward the optic nerve head, and upon contact of the fissure margins, dissolution of the basal lamina occurred and PAX2, known to be critical for this process, was expressed normally. Anterior closure was disrupted with the fissure margins failing to meet, or in some cases misaligning leading to a retinal lesion. These observations demonstrate, for the first time, a role for SALL2 in eye morphogenesis and that loss of function of the gene causes ocular coloboma in humans and mice.

• Blindness/diagnosis
• Blindness/epidemiology
• Blindness/etiology
• Blindness/rehabilitation
• Cataract/congenital
• Cataract/rehabilitation
• Child
• Developing Countries
• Glaucoma/congenital
• Glaucoma/rehabilitation
• Humans

To identify the sociodemographic characteristics, degree and cause of visual disability among certified visually disabled individuals in a rural district of West Bengal, India and to identify possible lacunae, if any, in the existing certification system.

A cross-sectional study by secondary data analysis of medical records of 155 visually disabled individuals and their 310 eyes. Demographical features, diagnosis, percentage of visual disability and work activity status of each individual were analyzed.

One hundred and thirty one (84.52%) individuals had 100% disability. The number of males was significantly higher than that of females. Fifty eight (37.42%) individuals were below 21 years of age. Phthisis bulbi was the most common cause followed by microphthalmos. Further, 81.29% patients had the same lesion bilaterally.

Patients with higher grades of disability have attended certification boards. A large number of disabled individuals comprised children and young adults. Male gender bias demands concern.

• Certification
• congenital abnormality
• visually impaired individuals

• Blindness/etiology
• Coloboma/complications
• Coloboma/diagnosis
• Coloboma/genetics
• Humans
• Uvea/abnormalities

• Adolescent
• Aphakia/epidemiology
• Blindness/epidemiology
• Blindness/etiology
• Cataract/epidemiology
• Child
• Corneal Diseases/epidemiology
• Eye Abnormalities/epidemiology
• Eyeglasses
• Female
• Humans
• India/epidemiology
• Male
• Retinal Diseases/epidemiology
• Vision Disorders/epidemiology
• Vision Disorders/etiology
• Visual Acuity/physiology

• Aldehyde Oxidoreductases/physiology
• Animals
• Body Patterning/physiology
• Embryonic Development
• Eye/cytology
• Eye/embryology
• Eye/growth & development
• Mesoderm
• Mice
• Mice, Knockout
• Models, Biological
• Morphogenesis/drug effects
• Paracrine Communication
• Tretinoin/pharmacology

• R01 EY013969 NEI NIH HHS
• R01 EY013969-04 NEI NIH HHS
• EY013969 NEI NIH HHS

• Adolescent
• Anophthalmos/genetics
• Anophthalmos/pathology
• Child
• DNA/chemistry
• DNA/genetics
• DNA Mutational Analysis
• Female
• HMGB Proteins/genetics
• Humans
• Infant
• Male
• Mutation
• SOXB1 Transcription Factors
• Syndrome
• Transcription Factors/genetics

• MC_U127527199 Medical Research Council

• coloboma
• aetiology
• genetics
• india

• Adolescent
• Child
• Child, Preschool
• Coloboma/complications
• Coloboma/epidemiology
• Coloboma/genetics
• Consanguinity
• Family Health
• Female
• Humans
• India/epidemiology
• Male
• Pedigree
• Risk Factors
• Siblings

• Adult
• Female
• Humans
• Pregnancy
• Pregnancy Trimesters
• Prenatal Diagnosis