Genetics and the

Many eye diseases are inherited or have familial clustering. It is, therefore, always advisable to enquire about the family history when interviewing a patient with an ophthalmological complaint. Some types of inherited eye disease lead to blindness and relatives of patients with such conditions often seek advice concerning their risk of developing the disease. Patients might also consult with a view to prenatal testing, particularly if the disease leads to blindness at a young age.

Recent advances in molecular biology have led to a dramatic increase in our understanding of eye diseases. The discovery and the unravelling of the role of numerous ocular disease genes has also helped in our understanding of normal eye development and functioning. Because of the advances made in ophthalmic molecular genetics, we are now able to refer to an inherited ocular condition not only by the mode of inheritance, but also to denote the abnormal chromosome, the abnormal gene's position on the chromosome and its nucleotide sequence. To date, over 150 different gene defects have been described for retinal conditions alone ( For many disorders, we also now know the role the abnormal gene plays in the pathogenesis of the disease, either because it leads to the production of an abnormally functioning protein or because the gene defect leads to the abnormal regulation of nearby or distant genes. Once the abnormal gene product (protein) associated with a disease can be identified, then drugs can be designed specifically, either to suppress its production or to replace the lost function.

Examples of eye disease that have been mapped out to different chromosomes are shown in Table 23.1.

Several methods are used in molecular biology to link disease to particular gene loci. Work usually starts by finding and classifying the disease in question in a large family or series of families. Next, the disease chromosome is sought (unless the inheritance pattern is X-linked, then this step can be omitted) and then the position of the gene in question is gradually narrowed down (by the use of linkage analysis followed by chromosome walking). This usually produces a region of the chromosome on which a number of candidate genes are found. Sequencing of these genes and comparison with normal individuals or animal models usually allows the disease gene to be identified (this can be a very time-consuming operation). Once the sequence of the gene is known, this can be compared on computer databases with similar known genes and the putative structure and function of the disease gene and its product can be determined. The potential of the latter has been greatly improved by the project to sequence the entire human genome.

Eye screening in selected patients at risk of inherited disease might detect important life-threatening conditions, for example familial adenomatous polyposis, retinoblastoma, Marfan's syndrome, neurofibromatosis and von Hippel Lindau disease.

Table 23.1. Chromosome mapping for common eye diseases 03


Eye disease


Leber's congenital amaurosis, Stargardt's disease, open-angle glaucoma (type 1A), congenital cataract,

retinitis pigmentosa


Congenital cataract, iris coloboma aniridia type 1, AR retinitis pigmentosa, congenital glaucoma


Usher's syndrome, AD retinitis pigmentosa


Treacher Collins mandibulofacial dysostosis


Goldenhar's syndrome


Aniridia type 2 (sporadic aniridia/Wilms tumour), Best's disease


Stickler's syndrome, congenital cataract




Neurofibromatosis type 1 (NF1;Von Recklinghausen's disease)


Neurofibromatosis type 2 (NF2)

X Chromosome

Ocular albinism

Juvenile retinoschisis

Norrie's disease


Retinitis pigmentosa

(Xq 28)

Colour blindness - blue cone, red cone, green cone

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