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HomemieyecareFamily History Genetics in Paediatric Eye Disease

Family History Genetics in Paediatric Eye Disease

Genetic causes underlie almost every eye disease ranging from paediatric syndromes through to common eye diseases such as age related macular degeneration, glaucoma, and myopia.

Professor David Mackey discusses the importance of establishing a thorough family history.

Eye diseases may have major genetic factors, usually regarded as mutations in Mendelian genes that are inherited in dominant, recessive or X-linked patterns. However, not everyone who carries the major gene mutation develops the disease (reduced penetrance) or the full spectrum of the disease (variable expressivity); other minor genetic influences or environmental factors explain this variation.

More commonly, diseases are due to a number of minor genetic changes (polygenic) that add up to cause a disease. An analogy for this would be that most diseases are like holding a bag of different coins of different values that can add up to $1, whereas some Mendelian diseases are like having a single $1 coin (Figure 1).

For paediatric eye diseases, we have explained much, but not all, of the underlying genetic architecture. Children with specific diseases, such as retinoblastoma, require genetic testing for best management of their families. Individuals with other conditions, such as congenital glaucoma and congenital cataracts, can also undergo genetic testing, but much of the time there is no clear answer. Research is ongoing, including advances in technology and understanding, so even if genetic testing in the past was negative, sometimes it is worth retesting with new gene arrays.


Taking a family history doesn’t end at the first consultation. Ask families to ask other family members about their eye health history. Often the extended family knows of conditions that the person in front of you doesn’t. Draw a family tree (male = square; female = circle; affected = shaded in). Ask about all brothers and sisters, their children, and parents, particularly on the maternal side where an X-linked inheritance pattern may be apparent (Figure 2). This approach can sometimes clinch the diagnosis without the need for extensive investigations, imaging, and genetic testing.

To practise drawing a family tree, one might consider looking at eye colour in an extended family with brown eyes dominant and blue eyes recessive or a family tree of colour blindness, which is X-linked recessive (Figure 3).2

Genetic testing can be ordered, but this often needs to be organised through a state-based genetic service or a genetic eye clinic.

Out-of-pocket costs can be considerable in some cases where patients wish to self-fund testing.


A new aspect of genetics in clinical practice is the issue of incidental findings. A person may have undergone testing for a non-ophthalmic disease but, incidentally, a mutation that causes an eye disease may be found (or vice versa). This could be a spurious result where the variant in an eye disease gene isn’t really a mutation but is just a benign variant (we often see this in people from minority ethnic groups where we have incomplete population genetic data). Alternatively, this could be a real disease-causing mutation, but the patient lacks other genetic variants to drive expression of the disease. A recently discovered example of this is that 1/1,000 people carry a Leber hereditary optic neuropathy mutation but only 1% of them lose vision.1


There is considerable literature on most genetic syndromes, see for example, Online Mendelian Inheritance in Man (OMIM).2

Numerous teaching resources are available to help explain genetics concepts, for example, ‘What colour are your eyes’3 and the American Academy of Ophthalmology (AAO) Basic and Clinical Sciences textbook volume two, which is regularly updated.4

It’s not what you know but knowing how to find out! There are so many diseases and so many genes that not even the genetic eye disease experts know them all.

You don’t need to know where genes are located on each chromosome, but you do need to know how to look up a gene and see if your patient has any of the features associated with that gene.

Gene-based therapy will continue to expand (e.g., it has been recently approved for Sickle cell anaemia in the United States). To enter a clinical trial, patients may need to register with a specific genetic eye disease registry or research institute, such as the Lions Eye Institute in Western Australia, Centre for Eye Research Australia in Victoria, and Save Sight Institute in New South Wales.

Keeping up on all advances will be impossible, but clinicians will need to have at least a broad understanding of risks, costs, and benefits of such therapy.

Professor David Mackey AO is a renowned international researcher in the genetics of eye disease and has published over 400 peer-reviewed papers since 1989. He is a National Health and Medical Research Council Practitioner Fellow, former Managing Director of the Lions Eye Institute (2009–19), a councillor of the Royal Australian and New Zealand College of Ophthalmologists (RANZCO), and current RANZCO representative on the Council of the Asia Pacific Academy of Ophthalmology and Vice President of APAO.


  1. Mackey, D.A., Ong, J.S., MacGregor, S., et al., Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low? Am J Hum Genet. 2023;110(1):170–6.
  2. Online Mendelian Inheritance in Man (OMIM), An online catalog of human genes and genetic disorders, available at: www.omim.org/.
  3. Mackey, D.A., What colour are your eyes? Teaching the genetics of eye colour & colour vision. Edridge Green Lecture RCOphth Annual Congress Glasgow May 2019. Eye (Lond). 2022;36(4):704–15. Available at: nature.com/articles/ s41433-021-01749-x [accessed 8 Nov 2023].
  4. Levine L.M., Brar, V.S., Mackey, D.A., et al., Genetics: Introduction, Chapter 5 (Molecular Genetics) and Chapter 6 (Clinical Genetics). Basic and Clinical Science Course, Section 2, 2018–2019 Fundamentals and principles of ophthalmology. ISBN 978-1-61525-555-6. Publisher: American Academy of Ophthalmology.