Chapter 18: Ophthalmic Genetics

INTRODUCTION

Ophthalmic genetics is concerned with pathogenesis, pattern of transmission, prognosis, and treatment of ophthalmic conditions due to genetic defects. Information on specific conditions, including the availability of genetic testing, is available online (eg, www.ncbi.nlm.nih.gov [National Center for Biotechnology Information] and www.genetest.org).

GENETIC DIAGNOSIS

A great number of ophthalmic conditions are transmitted through families in characteristic hereditary patterns. Others clearly have a genetic (chromosomal) basis but are rarely transmitted through more than one generation. Multigenerational genetic ophthalmic conditions are generally caused by limited deletions, mutations, and/or duplications of small segments of DNA on specific chromosomes, while those affecting only a single individual or a single generation are either due to large chromosomal abnormalities or an autosomal recessive condition.

Principal Patterns of Inheritance

The characteristic features of autosomal dominant inheritance are as follows:

1. The genetic abnormality is usually a small mutation in a single gene or small group of adjacent genes on one of the somatic chromosomes. The mutated gene is expressed in almost all individuals who inherit it regardless of the status of the corresponding gene inherited from the unaffected parent.

2. The genetic mutation and its associated condition are present in multiple consecutive generations (unless the condition is fatal before reproductive age).

3. The gene mutation is transmitted on average to half of the children of an affected person.

4. Males and females are affected equally.

Ophthalmic conditions and multisystem disorders with ophthalmic manifestations exhibiting autosomal dominant inheritance and their characteristic ophthalmic features are as follows:

1. Neurofibromatosis type 1: Iris Lisch nodules, multifocal choroidal melanocytic clusters, optic nerve and/or optic chiasm pilocytic astrocytoma (glioma), and periocular plexiform neurofibroma

2. Neurofibromatosis type 2: Combined retinal hamartoma

3. Tuberous sclerosis: Retinal astrocytoma (usually multifocal and bilateral)

4. von Hippel-Lindau disease: Retinal capillary hemangioma (usually multifocal and bilateral)

5. Retinoblastoma (usually multifocal and bilateral)

6. Best’s vitelliform macular dystrophy

7. Retinitis pigmentosa (some forms)

8. Gardner’s syndrome (familial adenomatous polyposis–carcinoma syndrome): Atypical nonclustered multifocal congenital hypertrophy of retinal pigment epithelium in both eyes

An isolated unilateral unifocal ophthalmic condition that is a feature of an autosomal dominantly inherited condition (eg, retinoblastoma, retinal capillary hemangioma, retinal astrocytoma, and optic nerve or optic chiasm glioma) is not always transmittable, because mutation of the relevant gene can develop in a normal chromosome after conception. If a mutation develops after conception and is present in the gamete (spermatozoa or ova), it can be transmitted to future generations as a novel mutation. Many conditions with an autosomal dominant pattern of inheritance are now known to be due to recessive mutations at the molecular level. The mutation is transmitted from one parent to his or her child but does not manifest unless the same or similar mutation is inherited from the other parent. Thus the clinical disorder develops only when there is a mutation on both chromosomes (recessive trait), but the ...