Myopia (nearsightedness) is a potentially blinding eye condition, and is the most common human eye disorder. Genetic studies of high-grade myopia- primarily performed by members of this consortium- are promising but limited, and historically have been small sample-size reports. Molecular genetic analyses of myopia in general have not been fully explored, and findings to date suggest a difference in genetic influences in high-grade myopia versus that of moderate myopia. The goal of my research is to gain a greater understanding of the molecular genetic basis of high-grade myopia. My research program was initially based on large-pedigree; family-based Mendelian trait myopia genetics in the United States, but in recent years has expanded to include international collaborations in Europe and Australia with other family studies, and twin studies. More recently we have developed collaborative projects studying refractive error genetics in large case-control and population studies in Singapore.
I hypothesize that the identification of myopia susceptibility genes will not only provide insight into the molecular basis of this significant eye disorder, but will also identify pathways that are involved in eye growth and development. This effort may lead to effective therapies to treat or potentially prevent this common eye condition
Identifying the genes contributing to the etiology of myopia is only a first step toward understanding the pathophysiology of this disease. It is equally important to understand how each of these etiological components interacts with each other. While tools to identify linkage and/or association exist and are being refined, tools to look for interactions between genes are still in their infancy. It will be important to consider the effect of interactions on risk, age at onset, and severity of disease. While the effect of a single gene may be determined independently, it is now important to examine any proposed susceptibility allele in relation to other known genes.
The identification of disease genes causing hereditary ophthalmologic disorders and associated anomalies is important for diagnosis and counseling, to aid in the development of therapeutic strategies, and to gain insight into the normal and abnormal development of the affected tissues. Hereditary ophthalmologic disorders may be syndromic (associated with other systemic findings), or non-syndromic (isolated). They may be inherited as autosomal recessive, autosomal dominant, X-linked, or mitochondrial traits. Syndromic forms of ophthalmologic disorders include blepharophimosis-ptosis-epicanthus -inversus syndrome (BPES), oculocutaneous albinism, Marfan syndrome, Stickler syndrome, CHARGE syndrome, etc. Non-syndromic forms of hereditary ophthalmologic disorders include microphthalmia, strabismus, congenital glaucoma, kerataconus, etc. Through the Pediatric Ophthalmic Genetics Clinical and Research Program at the Duke University Eye Center and the Center for Human Genetics, we recruit/ ascertain families and individuals with developmental hereditary ophthalmologic disorders to establish a comprehensive database and repository of patient DNA samples for use in the identification of the underlying molecular etiology.
The success of human genetic research, such as gene identification studies, depends on the ability to study human DNA and RNA, and corresponding demographic, clinical, and/or lifestyle data, when available. The Center for Human Genetics’ (CHG) DNA Bank serves as a repository for the ophthalmic genetics DNA samples and corresponding data for the current or future IRB-approved genetic studies conducted by Dr. Young and/or designated CHG/ Duke faculty members or outside collaborators.
We seek to identify the gene or genes responsible for developmental causes of blindness in the world. By identifying a gene and that gene's role in this process, new methods of treatment directed at the specific etiology of this disease will become possible. Benefit to the subjects involved in this study is most likely small. However, there may be substantial benefit to society in general by potentially reducing the tremendous cost of these disorders. Disorders that we have specifically focused on in our laboratory include: microphthalmia, anophthalmia, inherited strabismus, genetic syndromes with myopia as a phenotype (Wagner syndrome), and genotype/phenotype correlations in multi-system syndromes such as the craniofacial syndromes (Apert and Crouzon syndromes), cardio-facio-cutaneous syndrome, etc. We also recruit patients to participate in the National Eye Institute Eye- Gene program.
The present statistics of ophthalmic genetic disorders is impressive, and growing. Searching the Online Mendelian Inheritance in Man (OMIM) database (http://www.ncbi.nlm.nih.gov/omim) for the term “Eye” yields over 647 entries. (Mc Kusick, 1994) Winter’s diagnostic London Dysmorphology Database (LDDB) lists under the general term ‘Eyes, globes’ over 1800 syndromes and still unclassifiable single case reports. (Winter, 2001) Specific defects found in nearly 150 genes are associated with corneal and retinal dystrophies, eye tumors, retinitis pigmentosa, cataracts and glaucoma (http://www.ncbi.nlm.nih.gov/omim; http://www.sph.uth.tmc.edu/Retnet/disease.html). The characterization of gene mutations in specific eye diseases has aided in the identification of the abnormal proteins that cause disease, and expanded definitions of pathologic processes.
Several ophthalmic and systemic disorders with significant sight-threatening ophthalmic consequences now have identified gene mutations. Ophthalmologists, and in particular pediatric ophthalmologists, are often on the front-line in assessing patients and families with such disorders. Knowledge of clinical and molecular features of the disease- such as developmental age of onset, heritable probability, DNA testing parameters, and customized treatment options based on molecular insights and strategies- is paramount to excellent patient care.
Clinical Trials in Pediatric Ophthalmology
Dr. Young is an active participant in the Pediatric Eye Disease Investigator (PEDIG) program, and has enrolled and cared for multiple patients who have participated in this multi-enter, national collaborative research group. The purpose of these studies is to develop evidence-based protocols for pediatric ophthalmology and strabismus (pediatric and adult) evaluation and treatment practices.
