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

• Deep-phenotyping
• Eye genetics
• Gene editing
• Genetic counseling
• Molecular diagnostic testing
• Ocular gene therapy

• Humans
• Genetic Therapy/methods
• Eye Diseases/therapy
• Eye Diseases/genetics
• Animals
• Genetic Vectors
• Retinal Dystrophies/therapy
• Retinal Dystrophies/genetics
• Eye/pathology

• PAX6
• SHH
• SOX2
• TGFβ
• WNT
• ocular stem cells

• PAX6 Transcription Factor/metabolism
• PAX6 Transcription Factor/genetics
• Humans
• Animals
• Cell Differentiation
• Neural Plate/metabolism
• Eye/metabolism
• Stem Cells/metabolism
• Stem Cells/cytology
• Neural Stem Cells/metabolism
• Neural Stem Cells/cytology

• 2020-4772/SCR/ADHOC-BMS Indian Council of Medical Research

• anophthalmos
• bibliometric analysis
• microphthalmos
• network analysis

• embryonic stem cells
• ocular surface ectoderm
• single-cell transcriptomics
• surface ectoderm

• Anophthalmia
• Congenital
• orbito-facial disorders

• Anterior segment defects
• Intraocular lesions
• MR imaging
• Neuroimaging
• Ocular congenital malformations
• Ocular malignancy
• Posterior segment defects

• Child
• Humans
• Neuroimaging
• Embryonic Development

• Animals
• Retina
• Cell Differentiation/genetics
• Neurogenesis/genetics
• Stem Cells
• Vertebrates/genetics
• Gene Expression Regulation, Developmental/genetics

• R01 EY025933 NEI NIH HHS
• R01 EY031685 NEI NIH HHS

• ALDH1A3
• Behavioral abnormality
• Frameshift mutation
• Microphthalmia

• Gene Frequency
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Polymorphism, Single Nucleotide
• Refractive Errors/genetics
• Transcription Factors/genetics

• 206619/Z/17/Z Wellcome Trust
• MC_PC_17228 Medical Research Council
• MC_QA137853 Medical Research Council
• Fight for Sight

• Bipolar cells
• Cell fate
• Chromatin
• Neurogenesis
• PAX6
• Retina
• Super-enhancers
• VSX2

• Adult
• Animals
• Cell Differentiation/genetics
• Gene Expression Regulation, Developmental
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• Humans
• Mice
• Retina/metabolism
• Retinal Rod Photoreceptor Cells/metabolism
• Transcription Factors/metabolism

• P30 EY008098 NEI NIH HHS
• R01 EY029031 NEI NIH HHS
• R01 EY030861 NEI NIH HHS
• University of Pittsburgh
• Washington University in St Louis
• National Institutes of Health
• Research to Prevent Blindness
• National Institutes of Health (
• Eye and Ear Foundation of Pittsburgh

• Genetics
• Glaucoma

• TENM3
• coloboma
• gene
• microphthalmia
• mutation
• novel

• Microphthalmia
• OTX2
• prenatal diagnosis
• targeted gene sequencing panels

Regulation of gene expression by chromatin structure has been under intensive investigation, establishing nuclear organization and genome architecture as a potent and effective means of regulating developmental processes. The substantial growth in our knowledge of the molecular mechanisms underlying retinogenesis has been powered by several genome-wide based tools that mapped chromatin organization at multiple cellular and biochemical levels. Studies profiling the retinal epigenome and transcriptome have allowed the systematic annotation of putative cis-regulatory elements associated with transcriptional programs that drive retinal neural differentiation, laying the groundwork to understand spatiotemporal retinal gene regulation at a mechanistic level. In this review, we outline recent advances in our understanding of the chromatin architecture in the mammalian retina during development and disease. We focus on the emerging roles of non-coding regulatory elements in controlling retinal cell-type specific transcriptional programs, and discuss potential implications in untangling the etiology of eye-related disorders.

• cell fate
• enhancers
• epigenetics
• genome organization
• histones
• neurogenesis
• progenitors
• retina

Background: Coronary artery disease (CAD) is the leading cause of cardiovascular death. The competitive endogenous RNAs (ceRNAs) hypothesis is a new theory that explains the relationship between lncRNAs and miRNAs. The mechanism of ceRNAs in the pathological process of CAD has not been fully elucidated. The objective of this study was to explore the ceRNA mechanism in CAD using the integrative bioinformatics analysis and provide new research ideas for the occurrence and development of CAD.

Methods: The GSE113079 dataset was downloaded, and differentially expressed lncRNAs (DElncRNAs) and genes (DEGs) were identified using the limma package in the R language. Weighted gene correlation network analysis (WGCNA) was performed on DElncRNAs and DEGs to explore lncRNAs and genes associated with CAD. Functional enrichment analysis was performed on hub genes in the significant module identified via WGCNA. Four online databases, including TargetScan, miRDB, miRTarBase, and Starbase, combined with an online tool, miRWalk, were used to construct ceRNA regulatory networks.

Results: DEGs were clustered into ten co-expression modules with different colors using WGCNA. The brown module was identified as the key module with the highest correlation coefficient. 188 hub genes were identified in the brown module for functional enrichment analysis. DElncRNAs were clustered into sixteen modules, including seven modules related to CAD with the correlation coefficient more than 0.5. Three ceRNA networks were identified, including OIP5-AS1-miR-204-5p/miR-211-5p-SMOC1, OIP5-AS1-miR-92b-3p-DKK3, and OIP5-AS1-miR-25-3p-TMEM184B.

Conclusion: Three ceRNA regulatory networks identified in this study may play crucial roles in the occurrence and development of CAD, which provide novel insights into the ceRNA mechanism in CAD.

• WGCNA
• bioinformatics
• ceRNA
• coronary artery disease
• non-coding RNA

• OCLN gene
• cataract
• microcephaly
• microphthalmia
• prenatal diagnosis
• whole genome sequencing

14q22q23 microdeletion syndrome, also called Frias syndrome, is an extremely rare partial deletion of the long arm of chromosome 14 characterized by the anomalies of the pituitary gland, eyes, and hand/foot. Intellectual disability and facial dysmorphism are other common manifestations. Haploinsufficiency of the genes bone morphogenetic protein 4 (BMP4) and orthodenticle homeobox 2 (OTX2) accounts for most of the phenotypic abnormalities seen in these patients. There are only a few cases reported with Frias syndrome in the literature, and there are multiple variations present, which are not well recognized due to different set of genes involved. This case report presents the case of a young child with a deletion in 14q22.2q23.1 region containing both BMP4 and OTX2 genes as well as sineoculis homeobox homolog 1 (SIX1) and sineoculis homeobox homolog 6 (SIX6) genes. The case report illustrates the wide phenotypic findings associated with these genes along with additional unique findings that previously have not been commonly reported.

• 14q22q23 microdeletion syndrome
• anophthalmia
• bmp4
• chromosome 14
• facial dysmorphism
• frias syndrome
• global developmental delay
• otx2
• six1
• six6

• P30 AG062429 NIA NIH HHS
• National Institute on Aging
• National Institute of Neurological Disorders and Stroke

Skin disorders showing abnormal pigmentation are often difficult to manage because of their uncertain etiology or pathogenesis. Abnormal pigmentation is a common symptom accompanying aging skin. The association between skin aging and skin pigmentation abnormalities can be attributed to certain inherited disorders characterized by premature aging and abnormal pigmentation in the skin and some therapeutic modalities effective for both. Several molecular mechanisms, including oxidative stress, mitochondrial DNA mutations, DNA damage, telomere shortening, hormonal changes, and autophagy impairment, have been identified as involved in skin aging. Although each of these skin aging-related mechanisms are interconnected, this review examined the role of each mechanism in skin hyperpigmentation or hypopigmentation to propose the possible association between skin aging and pigmentation abnormalities.

• DNA damage
• autophagy impairment
• hormonal change
• oxidative stress
• skin aging
• skin pigmentation abnormalities
• telomere shortening

• Autophagy
• DNA Damage
• Humans
• Melanins/biosynthesis
• Melatonin/metabolism
• Oxidative Stress
• Skin Aging
• Skin Pigmentation/physiology
• Telomere Shortening

• Xenopus
• cells
• development
• eye
• human
• iPSC
• microphthalmia
• mouse
• optic vesicles
• organoids
• zebrafish

• 205174/Z/16/Z Wellcome Trust
• Moorfields Eye Charity

• anophthalmia
• genetic
• microphthalmia
• prosthesis
• whole-exome sequencing (WES)

• anophthalmia
• microphthalmia
• patient-reported outcome measures
• quality of life
• visual perceptual dysfunction

• MAC
• anophthalmia
• coloboma
• eye development
• microphthalmia

• clinical genetics
• genetics

• Genetic Loci
• Genetic Testing/methods
• Genetic Testing/standards
• High-Throughput Nucleotide Sequencing/methods
• High-Throughput Nucleotide Sequencing/standards
• Humans
• Microphthalmos/diagnosis
• Microphthalmos/genetics
• Mutation
• Sensitivity and Specificity
• Sequence Analysis, DNA/methods
• Sequence Analysis, DNA/standards

• Wellcome Trust
• 205174/Z/16/Z Wellcome Trust
• L60 MD003721 NIMHD NIH HHS
• NC/R001766/1 National Centre for the Replacement, Refinement and Reduction of Animals in Research
• Wellcome Trust (Wellcome)
• National Centre for the Replacement Refinement and Reduction of Animals in Research (NC3Rs)
• Federación Española de Enfermedades Raras (Spanish Federation for Rare Diseases)

• clinical genetics
• genetics

• OTX2
• SOX2
• anophthalmia
• coloboma
• development
• eye
• genes
• genetics
• induced pluripotent stem cells
• microphthalmia

• 205174/Z/16/Z Wellcome Trust

• SOX2
• anophthalmia
• microphthalmia
• suprasellar teratoma
• syndromic microphthalmia-3

• Biopsy
• Brain/abnormalities
• Brain/diagnostic imaging
• Child, Preschool
• Consanguinity
• Eye Abnormalities/diagnosis
• Eye Abnormalities/genetics
• Facies
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Imaging, Three-Dimensional
• Infant
• Infant, Newborn
• Magnetic Resonance Imaging
• Male
• Mutation
• Phenotype
• SOXB1 Transcription Factors/genetics
• Sequence Analysis, DNA
• Skull/abnormalities
• Skull/diagnostic imaging
• Teratoma/diagnosis
• Teratoma/genetics
• Tomography, X-Ray Computed
• Exome Sequencing

• Asociacion Para Evitar la Ceguera en Mexico
• Roberts Collaborative

• Animals
• Anophthalmos/genetics
• Genetic Association Studies/methods
• Genotype
• Humans
• Microphthalmos/genetics
• Phenotype
• Syndrome

Nanophthalmos is a clinical spectrum of disorders with a phenotypically small but structurally normal eye. These disorders present significant clinical challenges to ophthalmologists due to a high rate of secondary angle-closure glaucoma, spontaneous choroidal effusions, and perioperative complications with cataract and retinal surgeries. Nanophthalmos may present as a sporadic or familial disorder, with autosomal-dominant or recessive inheritance. To date, five genes (i.e., MFRP, TMEM98, PRSS56, BEST1, and CRB1) and two loci have been implicated in familial forms of nanophthalmos. Here, we review the definition of nanophthalmos, the clinical and pathogenic features of the condition, and the genetics of this disorder.

• anophthalmia
• coloboma
• exome
• microphthalmia
• nanophthalmos
• panel
• recessive

• Cataract/genetics
• Cohort Studies
• Connexins/genetics
• Eye Abnormalities/genetics
• Eye Proteins/genetics
• Female
• Gap Junctions/genetics
• Genetic Association Studies/methods
• Heterozygote
• Humans
• Lens, Crystalline/pathology
• Male
• Mutation, Missense/genetics
• Pedigree
• Phenotype

• BCL6
• BCOR
• Congenital cataract
• Oculofaciocardiodental (OFCD) syndrome

• vitamin a
• retinol
• hormones

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.

Microphthalmia and anophthalmia (MA) are congenital eye abnormalities that show an extremely high clinical and genetic complexity. In this study, we evaluated the implementation of whole exome sequencing (WES) for the genetic analysis of MA patients. This approach was used to investigate three unrelated families in which previous single‐gene analyses failed to identify the molecular cause.

A total of 47 genes previously associated with nonsyndromic MA were included in our panel. WES was performed in one affected patient from each family using the AmpliSeq^TM Exome technology and the Ion Proton^TM platform.

A novel heterozygous OTX2 missense mutation was identified in a patient showing bilateral anophthalmia who inherited the variant from a parent who was a carrier, but showed no sign of the condition. We also describe a new PAX6 missense variant in an autosomal‐dominant pedigree affected by mild bilateral microphthalmia showing high intrafamiliar variability, with germline mosaicism determined to be the most plausible molecular cause of the disease. Finally, a heterozygous missense mutation in RBP4 was found to be responsible in an isolated case of bilateral complex microphthalmia.

This study highlights that panel‐based WES is a reliable and effective strategy for the genetic diagnosis of MA. Furthermore, using this technique, the mutational spectrum of these diseases was broadened, with novel variants identified in each of the OTX2,PAX6, and RBP4 genes. Moreover, we report new cases of reduced penetrance, mosaicism, and variable phenotypic expressivity associated with MA, further demonstrating the heterogeneity of such disorders.

• Anophthalmia
• microphthalmia
• ophthalmology
• whole exome sequencing

• Glaucoma
• In vitro disease modeling/patient specific Induced pluripotent stem cell
• RNA-Seq
• Retinal ganglion cells
• SIX6

• Anophthalmia
• BMP4
• SALL4
• coloboma
• microphthalmia

• Coloboma/genetics
• Exome/genetics
• Female
• Growth Disorders/genetics
• Heart Septal Defects/genetics
• Humans
• Infant
• Microphthalmos/genetics
• Mutation, Missense
• Optic Nerve Diseases/congenital
• Optic Nerve Diseases/genetics
• Pedigree
• Phenotype
• Polymerase Chain Reaction
• Sequence Analysis, DNA
• Transcription Factors/genetics

• R21 EY019999 NEI NIH HHS
• R21 EY022779 NEI NIH HHS

The genetic causes of anophthalmia, microphthalmia and coloboma remain poorly understood. Missense mutations in Growth/Differentiation Factor 3 (GDF3) gene have previously been reported in patients with microphthalmia, iridial and retinal colobomas, Klippel-Feil anomaly with vertebral fusion, scoliosis, rudimentary 12th ribs and an anomalous right temporal bone. We used whole exome sequencing with a trio approach to study a female with unilateral anophthalmia, kyphoscoliosis and additional skeletal anomalies.

Exome sequencing revealed that the proposita was heterozygous for c.796C > T, predicting p.Arg266Cys, in GDF3. Sanger sequencing confirmed the mutation and showed that the unaffected mother was heterozygous for the same missense substitution.

Although transfection studies with the p.Arg266Cys mutation have shown that this amino acid substitution is likely to impair function, non-penetrance for the ocular defects was apparent in this family and has been observed in other families with sequence variants in GDF3. We conclude p.Arg266Cys and other GDF3 mutations can be non-penetrant, making pathogenicity more difficult to establish when sequence variants in this gene are present in patients with structural eye defects.

• Anophthalmia
• GDF3
• Growth/Differentiation Factor 3
• Microphthalmia
• p.Arg266Cys in GDF3