Introduction to Genetics for… series

Medicine is changing. The revolution in molecular genetics has fundamentally altered our notions of disease etiology and classification, and promises novel therapeutic interventions. Standard diagnostic approaches to disease focused entirely on clinical features and relatively crude clinical diagnostic tests.

Little account was traditionally taken of possible familial influences in disease.

The rapidity of the genetics revolution has left many physicians behind, particularly those whose medical education largely preceded its birth. Even for those who might have been aware of molecular genetics and its possible impact, the field was often viewed as highly specialist and not necessarily relevant to everyday clinical practice. Furthermore, while genetic disorders were viewed as representing a small minority of the total clinical load, it is now becoming clear that the opposite is true: few clinical conditions are totally without some genetic influence.

The physician will soon need to be as familiar with genetic testing as he/she is with routine hematology and biochemistry analysis. While rapid and routine testing in molecular genetics is still an evolving field, in many situations such tests are already routine and represent essential adjuncts to clinical diagnosis (a good example is cystic fibrosis).

This series of monographs is intended to bring specialists up to date in molecular genetics, both generally and also in very specific ways that are relevant to the given specialty. The aims are generally two-fold:

(i)to set the relevant specialty in the context of the new genetics in general and more specifically

(ii)to allow the specialist, with little experience of genetics or its nomenclature, an entry into the world of genetic testing as it pertains to his/her specialty

Genetics for Ophthalmologists

These monographs are not intended as comprehensive accounts of each specialty — such reference texts are already available. Emphasis has been placed on those disorders with a strong

genetic etiology and, in particular, those for which diagnostic testing is available.

The glossary is designed as a general introduction to molecular genetics and its language.

The revolution in genetics has been paralleled in recent years by the information revolution. The two complement each other, and the World Wide Web is a rich source of information about genetics. The following sites are highly recommended as sources of information:

1.PubMed. Free on-line database of medical literature. http://www.ncbi.nlm.nih.gov/PubMed/

2.NCBI. Main entry to genome databases and other information about the human genome project. http://www.ncbi.nlm.nih.gov/

3.OMIM. On line inheritance in Man. The On-line version of McKusick’s catalogue of Mendelian Disorders. Excellent links to PubMed and other databases. http://www.ncbi.nlm.nih.gov/omim/

4.Mutation database, Cardiff. http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html

5.Retnet. A listing of cloned and/or mapped genes causing retinal diseases. http://www.sph.uth.tmc.edu/Retnet/disease.htm

Eli Hatchwell

Cold Spring Harbor Laboratory

Introduction

Preface

A decade ago, it was unimaginable that the entire genomic sequence would be completed within a few years. The identification and mapping of our genes has already led to a better understanding of their expression and function.

Over this period a vast number of genes underlying monogenic ophthalmic disorders have been identified and our understanding of disorders affecting every part of the eye has been enhanced immeasurably. As genetic testing technologies become more readily available and accessible as an aid to both diagnosis and management, the impact on the practice of ophthalmology will be profound. As a result, an understanding of its power and capabilities has become essential.

A working knowledge of the practice of genetics has become relevant and should no longer be regarded as a quaint academic pursuit. Furthermore, its importance should not be underestimated: in pediatric ophthalmology, around half (probably more) of the cases of childhood blindness have a genetic cause, while inherited factors contribute to the blinding effects of adult-onset diseases such as diabetes, glaucoma and age-related macular degeneration. As is clear from the clinical sections, awareness of extraocular manifestations is crucial to the diagnosis and correct management of many of the conditions in this book. Therefore, ophthalmologists must think broadly when approaching their genetic patients: without consideration of cardiac complications, the management of ectopia lentis in Marfan syndrome will not meet all of that patient’s needs. The same is true of the need for sun protection in albinism, or tumor surveillance in those with von Hippel Lindau disease.

Fortunately, encyclopedic knowledge is not required. As with any branch of clinical medicine there are generalized principles in the approach to, and management of, inherited disorders whose understanding enables both the generalist and the subspecialist to deal in a standardized – and reliable – fashion with the often

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complex problems that are posed by genetic disease. The purpose of this book is to present current knowledge of a range of inherited ocular disorders in a concise, approachable format to enable the clinician to gather easily a working knowledge of the clinical manifestations and molecular features of each disorder. It is primarily aimed at the ophthalmologist but it will also be useful to trainees at all levels as well as clinical geneticists and molecular scientists who share an interest in genetic ophthalmology.

Genetic testing

An increasing number of genes are being cloned that are responsible for inherited ophthalmic conditions. While it is assumed – especially by patients and their families – that gene identification is followed closely and inevitably by routinely available genetic testing, this has been shown repeatedly not to be the case. The time lag leads to a significant gulf between the expectations of patients and the abilities of the clinician to fulfil them. There are a number of factors to consider:

•Screening for mutations in most genes is a labor-intensive and time-consuming process that requires analysis of the whole gene. Exceptions to this are TIMP3 (Sorsby dystrophy) and

BIGH3 (stromal corneal dystrophies) where the range of mutations is limited. Therefore, in the majority of cases screening may take a number of months.

•In conditions where a broad range of genes may cause an identical phenotype (e.g. retinitis pigmentosa) there is no way to ascertain which gene is responsible; this makes screening impractical in a clinical setting, using current techniques.

•Mutation detection procedures are not 100% sensitive. Many methods of identifying mutations within a gene are ~70% successful. Therefore, in many cases molecular analysis will not produce a ‘definitive’ result.

Where mutation screening is appropriate, blood samples are usually

only taken from an affected member of the family: mutation

Preface

screening of an unaffected family member is only of use once a mutation is found. Therefore, in a proportion of families that are seen, mutation screening is not available because a sample cannot be obtained from an affected member of the family. A negative result in an unaffected person may mean that a mutation is not present, or for technical reasons a mutation has not been detected, or that a mutation may be present in another gene.

Genetic testing has come to mean mutation testing in the eyes of many. However, it should not be forgotten that chromosome analysis (karyotyping) is an important tool which, when used selectively in the correct circumstances, is critical to the management and diagnosis of many genetic conditions (see ‘karyotype’ in the glossary).

Predictive testing

Examining relatives in the clinic can be a valuable adjunct to diagnosis. This is true for both static, developmental disorders (congenital cataract, coloboma) and progressive disorders (retinal dystrophies). However, when faced with expectant, as yet unaffected, relatives or children what should the clinician do?

Within genetic centers, protocols are in place for predictive testing (either through examination or genetic testing) in families with adult-onset genetic disorders. These are based on protocols for testing in families with Huntington disease. They include discussion of the risks associated with mutations, the implications to the wider family of a mutation result and a discussion of how patients may cope with a ‘bad’ news result that confirms a high risk of developing symptoms. Patients are advised to seek financial advice, as the situation with regard to access to results for insurance companies is currently uncertain. Within the ophthalmic setting there has been little consideration of the potential impact of presymptomatic genetic diagnosis – either through examination or genetic testing. It should be remembered that the aim of testing must be to improve diagnosis and management, and to facilitate counselling of patients and their families. Clearly, if such a test disadvantages patients then it fails to meet these aims.

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Therefore, consideration needs to be given to the clinical need for genetic testing, and patients and their relatives need to understand the pros and cons of such a process. When approaching asymptomatic at-risk relatives it may be useful to ask these questions prior to examining or drawing blood:

•Is there a clinical need in proceeding with presymptomatic diagnosis?

•Does it need to be done now? (What is done can never be undone.)

•Are there disadvantages to presymptomatic diagnosis (psychological, employment, financial)?

•Does the patient really want to know?

Genetic counselling

The aim of genetic counselling is to inform patients and their families about how and why a condition affects them now and in the future, and to explain its reproductive implications. This is not simply a question of defining risks and explaining inheritance patterns. Fundamental to any counselling process is accurate clinical diagnosis and, within a genetic ophthalmic clinic, the clinician must be prepared to modify or even to change a previous diagnosis.

Such a process takes time and an appropriate clinical setting is required such as a clinical genetic or joint genetic-ophthalmic clinic. Such a consultation will then allow accurate history/family history taking, examination (often of multiple family members), discussion, explanation and answering patients’ questions.

Finally, when approaching genetic counselling, the expectations of the patient must be considered. It is important to understand what they are seeking and why they may be unsatisfied at the end of the process. Through the power of the internet, as well as the many excellent patient organizations, those with inherited ocular disorders are often well informed about their conditions – perhaps more

Preface

up-to-date than their physicians! While information is often what they require, either by way of confirmation or reassurance, two specific themes recur. Firstly, patients will often want genetic testing to define the risks to offspring. Sadly, current techniques often make this either impossible or unlikely to be successful. Secondly, and perhaps more importantly, patients are often keen to seek novel treatments that will either prevent or restore loss of sight. The latter is strongly fuelled by frenetic media coverage and leads to unrealistic expectations. In any counselling setting it is important to feel comfortable giving bad news. It is in no-one’s interest to be unrealistically optimistic about future prospects. Total pessimism is similarly unhelpful. Therefore, ‘cautious realism’ in explaining that hope for the future may not, in fact, be translated into practical help for the present is often important in helping families come to terms with the reality of a situation and in enabling them to begin to prepare for the future.

Genetics for Ophthalmologists