Hereditary eye diseases have become a leading cause of blindness among children and adolescents. Ophthalmic genetics primarily focuses on studying the inheritance patterns, mechanisms of pathogenesis, and potential prevention and treatment strategies for hereditary eye diseases and systemic genetic disorders with ocular manifestations.
Clinical Genetics
Based on the mode of inheritance and the relationship with genetic material, hereditary eye diseases can be classified into three major categories: monogenic disorders caused by mutations in a single gene; polygenic disorders involving multiple genetic loci, where environmental factors play a significant role in disease manifestation (also termed multifactorial genetic diseases); and chromosomal disorders resulting from numerical or structural abnormalities, also known as chromosomal syndromes or chromosomal aberration syndromes. Among hereditary diseases with ocular involvement, monogenic disorders account for the majority. These include autosomal recessive conditions such as high myopia and galactosemia, autosomal dominant conditions such as congenital ptosis and Marfan syndrome, and X-linked hereditary disorders such as red-green color blindness, ocular albinism, and primary congenital nystagmus. Polygenic hereditary eye diseases, or diseases likely to be polygenic, include simple myopia, primary glaucoma, and concomitant strabismus, which often have high prevalence rates.
The causes and inheritance patterns of many of these eye diseases are complex and may sometimes be difficult to distinguish from acquired diseases. Diseases caused by chromosomal abnormalities often manifest as systemic syndromes, such as Down syndrome accompanied by ocular morphological changes. Disorders associated with structural chromosomal changes include conditions like retinoblastoma. Individuals whose genetic makeup predisposes them to a certain disease or type of disease exhibit what is known as genetic susceptibility. For example, some individuals are more prone to spring catarrhal conjunctivitis. Different pathogenic genes can lead to the same clinical manifestation. For instance, retinitis pigmentosa can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern, yet presents with similar or identical clinical features—a phenomenon referred to as genetic heterogeneity. This heterogeneity is significant for accurate determination of the mode of inheritance and calculating the probability of disease occurrence in offspring or relatives, which is the basis of genetic counseling. Non-genetic or environmental factors that cause variations resembling those of genetic mutations are termed phenocopies. An example is congenital cataracts caused by maternal rubella virus infection, which are clinically indistinguishable from genetically inherited congenital cataracts.
Research Methods in Hereditary Eye Diseases
Several research methods are used in clinical studies of hereditary eye diseases:
Family Pedigree Analysis
This method involves constructing and analyzing pedigrees to determine whether a condition is hereditary and, if so, the mode of inheritance.
Twin Studies
Twin studies enable comparisons between genetic and environmental effects and facilitate the calculation of heritability indices for diseases.
Interracial Comparisons
Since genetic differences exist between populations, certain diseases show variability in prevalence, clinical presentations, age of onset, and sex distribution among different racial groups. For example, angle-closure glaucoma is more prevalent among Asian populations, while open-angle glaucoma predominates among Caucasians of European and American descent.
Co-segregation Studies
The concurrent presence of a condition with a known genetic trait or disorder can indicate a genetic basis for the condition.
Disease Component Analysis
This involves analyzing specific aspects or components of complex diseases to determine the role of genetic factors.
In addition to these methods, the establishment of animal models for human diseases, particularly spontaneous animal disease models or transgenic animal models, can facilitate research on the pathogenesis, clinical progression, manifestations, and experimental treatments of hereditary eye diseases.
Molecular Genetics
In recent years, advancements in molecular biology—especially in the construction of genomic DNA libraries, nucleic acid hybridization, DNA sequencing technologies, polymerase chain reaction (PCR), and recombinant DNA technology—have brought revolutionary changes to the field of medical genetics. Within ophthalmology, these developments have significantly enhanced the study and application of the pathogenesis (e.g., gene localization), diagnosis (e.g., gene mutation detection), and treatment (e.g., gene transfer) of hereditary eye diseases. Molecular biology techniques have identified that Leber’s hereditary optic neuropathy is caused by mitochondrial DNA (mtDNA) mutations. Genes responsible for primary open-angle glaucoma have been mapped to loci such as GLC1 and GLC3. Molecular genetics has revealed that 70% of retinoblastoma cases involve allelic loss of heterozygosity, and esterase D (EsD), the only known polypeptidase located on chromosome 13q14, is currently used to detect defective genes in retinoblastoma. EsD polymorphisms are also utilized as genetic markers in familial linkage analysis, enabling prenatal diagnosis of retinoblastoma and aiding genetic counseling.
In 2006, international efforts made breakthroughs in identifying genes associated with age-related macular degeneration (AMD). The fundamental treatment of hereditary eye diseases involves gene replacement therapy (gene correction or substitution). This therapy delivers normal genes to produce functional gene products, thus correcting enzyme or protein defects caused by disease-causing genes. Gene therapy research for hereditary eye diseases, such as treatment for retinal degeneration in transgenic mice, has already commenced. With ongoing progress in molecular genetics and molecular biology, it is anticipated that gene therapy for hereditary eye diseases will soon find clinical applications.
Epigenetics
Epigenetics, a burgeoning field in recent years, pertains to heritable variations affecting gene expression or cellular phenotype that are not dictated by changes in the DNA sequence itself. In multicellular organisms, every cell contains the same DNA sequence, yet distinct terminal phenotypes are maintained. Such "memory" of cellular identity—independent of the genomic DNA—records the impacts of development and environmental factors, thereby representing the essence of epigenetics.
Well-known epigenetic phenomena include DNA methylation, histone modification, chromatin remodeling, and the regulation of gene expression by noncoding RNAs. Epigenetic variations have been implicated in numerous human diseases, particularly cancers. Interestingly, retinoblastoma was one of the first diseases in which oncogenic epigenetic variations were discovered. To date, most diseases, especially complex ones, cannot be fully explained by genetic variations in the genomic DNA. It is hypothesized that many such conditions can be partially explained by nongenomic hereditary factors—that is, epigenetics.
Throughout development and aging, environmental factors induce epigenetic variations in the body, influencing cellular transcription levels. These variations can remain stable over a lifetime and even pass to the next generation, potentially affecting susceptibility to diseases. This could partly explain the onset of common, slowly progressing diseases in middle-aged and older adults, such as primary glaucoma and AMD. Furthermore, as a consequence of environmental influences, epigenetic modifications provide insights into how non-genetic factors, such as diet, smoking, and environmental pollution, increase disease risk and susceptibility.
Current understanding of the relationship between epigenetics and ocular development or diseases remains limited. It has been established that DNA methylation plays a role during eye development. Photoreceptor-specific genes exhibit cell-specific DNA methylation patterns. Histone modifications have been observed in pathological retinal ganglion cell damage following optic nerve injury and in the progression of diabetic retinopathy.
Understanding the relationship between epigenetics and diseases may uncover new therapeutic approaches. For example, inhibitors of methyltransferases, histone acetyltransferases, and histone deacetylases (HDACs) can potentially modulate gene expression. In oncology, HDAC inhibitors induce a state of hyperacetylation in rapidly dividing tumor cells, leading to apoptosis. However, the effects of HDAC inhibitors in neurons are the opposite. For instance, in neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, HDAC inhibitors have been shown to reduce neuronal loss. Similarly, neuroprotective effects of HDAC inhibitors have been observed in animal models of optic nerve injury and ischemia, although the precise mechanisms remain unclear.