The eye is affected in about one-quarter of all inherited diseases, thus possible genetic causes of eye malformations must be considered. Congenital A/M can occur alone or with other birth differences. Geneticists use unusual findings in the eye, as well as other findings throughout the body, to help identify possible syndromes or causes of the disorder in an individual.

A/M has many different potential causes, including genetic conditions such as chromosomal disorders and single gene disorders.

Chromosomes are tiny structures that carry our genetic information and are arranged in 23 pairs in each cell of the body. One chromosome of each pair comes from the mother and the other from the father. Each chromosome consists of thousands of genes, which are made up of DNA. The DNA is the genetic “alphabet” consisting of four letters: A, C, T and G. These letters create a series of three-letter “words” that combine and make up genes. Each gene has a specific function to encode the directions for the production of proteins in our bodies. Proteins are elements that do the different jobs our bodies require. A change in any of these “words” is known as a mutation. A mutation can lead to either abnormally made proteins or absence of the protein which then affects the development of the fetus during pregnancy.

Single gene disorders occur as a result of a mutation in one gene on one or both of the chromosomes of a pair. This mutation changes the genetic information and therefore the blueprint for development, which leads to disease or birth defects.

Chromosomal disorders involve extra or missing chromosomes, or rearranged pieces of chromosomes. This extra or missing information changes the blueprint for development. Because each chromosome houses thousands of genes, a normal chromosome result cannot tell us if all the genes are working properly. It simply tells us there are no large pieces of chromosomes that are extra, missing or rearranged.

Sometimes, we cannot identify a syndrome in an individual to help explain the cause of A/M. Researchers are currently working on locating the gene or genes involved in normal eye development, which may lead to many answers about anophthalmia and enable geneticists to provide more accurate counseling and recurrence risks.

Identifying Genes that may cause anophthalmia, microphthalmia and coloboma

Development of the eye during pregnancy is a very complex process. Many genes are involved in ensuring that the sequence of this development occurs as it should. The eye is completely developed in the first trimester of pregnancy.

There are many known causes of anophthalmia, microphthalmia and coloboma including genetic conditions and prenatal exposures to infections and medicines. However, in most cases the cause is unclear.

Genetic research

Researchers around the world are working to identify the genes involved in the normal development of the eye. Many genes have been found to have a role in this complicated process. Changes in these genes, also known as mutations, can cause the gene to not work properly causing abnormal development of the eye.

Most changes (mutations) in a gene have occurred for the first time in the individuals with anophthalmia/microphthamia. In other words there is no family history of the condition. This does not mean the cause is not genetic.

Identifying the cause of the eye defect is important in terms of management of the individual medically and educationally. In addition, risks for recurrence differ based on the reason that the eye defect occurred.

SOX2 Gene

What is SOX2 syndrome?

People with SOX2 syndrome are usually born with anophthalmia, although some individuals have microphthalmia. The anophthalmia or microphthalmia can be in one eye or both.

Individuals with SOX2 syndrome may also have seizures, brain abnormalities, slow growth, delayed development of motor skills (such as walking), and mild to severe learning disabilities. Some people with this condition are born with a blocked esophagus (esophageal atresia), which is often accompanied by an abnormal connection between the esophagus and the trachea (tracheoesophageal fistula). Genital abnormalities have been described in affected individuals, especially males.

How common is SOX2 syndrome?

SOX2 syndrome is estimated to affect 1 in 250,000 individuals. About 10 percent to 15 percent of people with anophthalmia in both eyes have SOX2 syndrome.

How do people inherit SOX2 syndrome?

Mutations in the SOX2 gene cause SOX2 syndrome and is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the SOX2 gene. This means there is no history of the disorder in their family. In a small number of cases, people with SOX2 syndrome have inherited the changed gene from an unaffected parent who has a SOX2 mutation only in their sperm or egg cells. This phenomenon is called germline mosaicism.

This gene was identified several years ago by researchers in England. Changes (mutations) in this gene have been found in about 15% of individuals with anophthalmia/microphthalmia. Typically an individuals has 2 working copies of this gene. If one copy is changed (mutated) it leads to anophthalmia/microphthalmia. Genetic testing is available for SOX2 and should be ordered on anyone with anophthalmia or microphthalmia. If you need help getting this test done call Adele Schneider 215-456-8726 or e-mail schneida@einstein.edu.

Einstein Philadelphia Genetic Registry Study

There are many genes involved in the development of the eye and mutations have been identified in many of them.

Since 1993, Dr. Adele Schneider, head of Genetics  at Einstein Healthcare Philadelphia, has been collecting clinical information and DNA samples on individuals with anophthalmia, microphthalmia and coloboma, through the Anophthalmia / Microphthalmia (A/M) Clinical and DNA Research Study.

Their website at www.einstein.edu/genetics/programs/anophthalmia-microphthalmia-registry gives detailed information about the study, and their latest Consent Form gives even more detail.

Dr. Schneider is the PI (Principal Investigator) of this research. Sarina Kopinsky is the research coordinator / genetic counselor. They can be reached at 215-456-8722, kopinsks@einstein.edu.Please contact them if you want more information or if you have any questions or to request a copy of the consent form.

In summary, the study is seeking genetic causes of anophthalmia, microphthalmia and coloboma. They are gathering medical details about the symptoms (e.g., one or both eyes, anophthalmia vs. microphthalmia, with or without other medical problems or ocular conditions, with or without a family history), studying the results of DNA genetic testing, arranging genetic testing if needed, and looking for correlations between the genetic results and the medical symptoms. The study also coordinates genetic testing at clinical laboratories and collaborates closely with each person’s local genetics department.  The A/M Registry at Einstein stores both sets of information in one database – the medical records and the genetic testing details.

The Division of Genetics at Einstein offers a genetics clinic in Philadelphia where people with A/M can be seen as clinical patients, if the location is convenient. Or else they encourage each family to make an appointment at a local genetics department near their home. They are happy to assist you with a referral to a local genetics department, and to communicate with them about your care and your participation in their research.

Some genetic tests can be performed at the laboratories of Einstein’s research partners. Research testing is free but it is very slow, and is not available for all the necessary tests. Certain tests that used to be available only on a research basis are now available clinically and some insurance plans cover them.

Typically, microarray is the first genetic diagnostic test ordered for a baby with A/M. Microarray gets ordered clinically, since it is no longer available on a research basis.

Einstein clinic patients do not have to enroll in the Einstein research study and people enrolled in their study do not have to choose Einstein Genetics for their clinical care. Similarly, ican members are not required to choose Einstein Genetics for their clinical appointments or to enroll in the Einstein research study. Each entity is separate.

There are many other genes involved in the development of the eye and mutations have been identified in many of them. Dr. Adele Schneider has been collecting clinical information, with or without DNA samples, on individuals with anophthlamia, microphthalmia and coloboma, through the A/M Registry Research Project. The study aims to study any correlations between the clinical symptoms and the genetic findings. Any research findings need to be confirmed in a clinical laboratory, using insurance, with the help of a local geneticist and genetic counselor.

If you want more information or if you have any questions, please contact the genetic counselor / research coordinator, Sarina Kopinsky, MS, LCGC, 215-456-8726 or e-mail kopinsks@einstein.edu.