Professor Nicola Ragge

Consultant Clinical Geneticist

Clinical Genetics Unit

West Midlands Regional Clinical Genetics Service

              The Genetics of Bilateral Anophthalmia

Around 30 in 100,000 children are born with both of their eyes missing, a condition also known as bilateral anophthalmia (BA). BA is part of a spectrum of eye anomalies that also includes, Microphthalmia (small eye) and Coloboma (gap in one or more layers of the eye structures), and collectively these conditions are referred to as AMC (Anophthalmia, Microphthalmia, Coloboma). Bilateral anophthalmia can be associated with other birth anomalies and developmental issues in over half of individuals.  The impact on the individual and their family is immense, since there may be a combination of visual impairment, cosmetic and other major health issues, including developmental delay, autistic spectrum disorder, heart, kidney and/or limb anomalies.  Additionally there may be a concern about recurrence risk (whether another family member could be affected in the future) and this would depend on the underlying diagnosis. 

For many individuals with bilateral anophthalmia, genetic alterations in key genes that help to develop the human eye and other organs may underlie the condition. Each gene is associated with its own inheritance pattern – dominant, recessive or X-linked (for a detailed explanation see below). Therefore identification of an underlying genetic cause enables accurate assessment of recurrence risk, and the possibility of prenatal testing, or pre-implantation genetic diagnosis.

Research into the Genetics of Bilateral Anophthalmia (BA)

Professor Nicola Ragge, who is a Consultant Clinical Geneticist at the West Midlands Regional Genetics Service, and is also an experienced paediatric and adult ophthalmologist, has been conducting research into the genetics of developmental eye anomalies, and specifically anophthalmia, since 1999. She played a key role in the initial identification of the two genes most frequently altered in BA, SOX2 and OTX2, thus changing the whole perception of the genetic basis for eye anomalies. She and her team have continued to identify new genes and syndromes associated with AMC, helping to define a new field of research and clinical practice, that of developmental ocular genetics.  Through a worldwide effort, over 112 genes have been linked directly to conditions with AMC, and there are at least another 45 genes implicated in publications describing findings from 1 or 2 families.

For best medical management of a new baby or affected individual, rapid genetic diagnosis is of paramount importance. This will allow early screening for relevant conditions, and also give an accurate estimate of recurrence risk and genetic counselling. To enable genetic diagnosis, Professor Ragge has pioneered two diagnostic methods testing over 350 genes involved in eye development, in collaboration with the NHS West Midlands Regional Genetics Service based at Birmingham Women’s and Children’s Foundation Hospital Trust. These tests include the customised eye array – which detects structural changes of the chromosomes (the bodies that carry our genes) or the eye development genes themselves. Another test is the eye gene panel or whole exome sequencing (testing all the genes) – which detects sequence variants (“spelling alterations”) in these 350 eye development genes. These tests are currently available through the West Midlands Regional Genetics Service and will form the basis of standardised, genetic testing for structural eye disorders (analysing 112 genes) that will be implemented by NHS England in 2020 available to all families.  

Genes associated with Bilateral Anophthalmia

It is now thought that in most individuals with BA, the absence of the eyes may eventually be explained by an alteration in one of the genes that directs eye development. Currently, around 70% of individuals with BA that are being seen by Professor Ragge will receive a genetic diagnosis. The most commonly altered genes in BA are SOX2, OTX2, ALDH1A3, STRA6 and BCOR. 

SOX2 

This is altered in around 15-30% of individuals with BA. Affected individuals usually (but not always) have severe bilateral eye anomalies. They also frequently have delayed development and growth, which can be linked to pituitary problems, kidney problems, underdeveloped sexual organs and occasionally malformation of the oesophagus (anophthalmia-esophageal-genital [AEG] syndrome). SOX2 gene alterations are dominantly inherited gene, meaning that an alteration in one of the copies is enough to cause BA.  

OTX2

Genetic alterations in the OTX2 gene are identified in around 10% of individuals with BA.  Individuals with OTX2 gene alterations can have several eye anomalies. These can be bilateral anophthalmia, or another condition called Leber’s congenital amaurosis, which is an early onset retinal degenerative condition associated with severe visual impairment in early life.  Some individuals with OTX2 alterations may also have developmental delay, growth and pituitary problems and hearing loss. 

ALDH1A3 and STRA6 genes

The ALDH1A3 and STRA6 genes both code for proteins that are part of the biological pathway that processes vitamin A. Unlike SOX2 and OTX2, affected individuals usually have alterations in both copies of the gene (recessive inheritance). Some individuals with alterations in these genes do not have any other health problems, while others might have delayed development and/or autism (ALDH1A3) or severe heart and lung problems, diaphragmatic hernia and kidney problems (STRA6). 

BCOR

The BCOR gene is located on the X chromosome. To recap, females have two X chromosomes, and males, an X and a Y chromosome, so are affected differently by genes that are carried on the X chromosome.

Alterations in the BCOR gene give rise to two different conditions depending on whether the affected individual is male or female. Females with an alteration in their BCOR gene have a condition called Oculo-Facio-Cardio-Dental (OFCD) syndrome. They usually have microphthalmia and cataracts, but also as the name suggests, facial, heart and tooth anomalies, as well as some other features, including skeletal anomalies. 

Genetic counselling: The BCOR alterations affecting males can occur new in the individual, when the recurrence risk would be low.  Some affected males have inherited from their unaffected mother, who would then be a carrier.  In this situation, if the mother has a male child, there would a 50% chance of that male being affected; if they have a female child there would be a 50% chance she would be a carrier (but unaffected) female child.  If affected males with BA caused by BCOR alterations have children, their male children will inherit their Y chromosome and therefore be unaffected, and their female children will inherited the X chromosome carrying the altered BCOR gene and will be carriers.  Genetic counselling is important as there may be unaffected female carriers in the family would be benefit from genetic advice and testing. Prenatal testing and pre-implantation genetic diagnosis (PGD) would be available in the UK. 

Genetics Advice

As BA has a highly complex genetic aetiology, it is advisable for families to be seen by a geneticist specialising in structural eye anomalies. Although a few examples have been given above, other genes may be involved.  The testing involves over 100 genes, and the results can sometimes be more complicated than described above.  With over 20 years experience, Professor Ragge is one of the few specialists in the UK.  She accepts referrals from throughout the United Kingdom and offers access to the AMC-specific diagnostic tests at the West Midlands Regional Genetics Service, and from next year will be part of one of the 3 national specialist eye genetics testing centres. For families that do not receive a diagnosis through these diagnostic methods, Professor Ragge offers further state-of-the-art testing through her research programme in Oxford.

For families, receiving a genetic diagnosis can be an enormous help, as this provides an explanation for their own or their child’s anophthalmia. This may in turn provide welcome reassurance regarding any other pregnancy factors that families might have thought had contributed to their child’s anophthalmia. The diagnosis will also enable them to understand the features and the prognosis of the condition, and access appropriate screening and management of associated medical conditions.  Screening for some of these conditions, including for example, kidney, or heart anomalies, or delayed growth or development can be very beneficial, and in some circumstances life-saving.  For families wishing to extend their families, having already had an affected child, a diagnosis provides accurate information on recurrence risk for future children, and the offer of prenatal and/or pre-implantation diagnosis. Most importantly, having a diagnosis, and the knowledge that the anophthalmia and potential other health problems are part of a known syndrome, may aid in accessing health, visual impairment, school, social and financial support and will allow families to be in contact with others affected by the same condition and support groups. 

Professor Ragge is happy to accept referrals from any part of the United Kingdom. Referrals should be sent through the NHS E-RS system (please ask your GP to look for: Clinical Genetics RAS  -  Birmingham Women’s Hospital  RLU).  Details for Professor Ragge:

Professor Nicola Ragge MD, FRCPCH, FRCP, FRCOphth

Consultant Clinical Geneticist

Clinical Genetics Unit

West Midlands Regional Clinical Genetics Service

Birmingham Women's and Children’s NHS Foundation Trust

Mindelsohn Way

Edgbaston

Birmingham

B15 2TG

If you wish to take part please contact

Secretaries (Birmingham):

tel. 0121 335 8024

Email: genetics.info@nhs.net

If you have any further questions about participating in the research study, you are most welcome to speak to her research co-ordinators in Oxford, Dr Dorine Bax (01865 534923) and Dr Fiona Watkins (01865 803045), eye.genetics.study@brookes.ac.uk or contact Professor Ragge through ragge.eye.study@me.com

The genetics service provides testing and counselling for patients and families with inherited eye disease.

Genetic testing can be used to find out whether a person is carrying a specific altered gene (genetic mutation) that causes a particular eye condition. It may be carried out for a number of reasons, including to:

Diagnose a person with a genetic condition.

Help work out the chances of a person developing a particular condition.

Determine whether a person is a carrier of a certain genetic mutation that could be inherited by any children they have.

If your doctor thinks genetic testing may be appropriate for you, you'll usually be referred for genetic counselling as well. Genetic counselling is a service that provides support, information and advice about genetic conditions. It's conducted by healthcare professionals who've received training in the science of human genetics (a genetic counsellor or a clinical geneticist)  

You should speak to your consultant eye doctor, GP or optician if you think you need genetic testing. If he or she decides that your condition needs to be investigated by more specialist staff, they will arrange for you to have an outpatient appointment with Moorfields or another provider. If you choose to be treated at Moorfields, we will send you a letter confirming the date, time and location of your appointment with us.