Background

In developed countries, half of the conditions causing childhood blind and partially sighted registration are genetic,^1–3 a figure that is likely to be underestimated. In many developing countries where childhood visual disability is significantly commoner, genetic conditions also represent an important group contributing to childhood blindness.^1,4–6 “Genetic” conditions referred to in this context are monogenic, (Mendelian) conditions. Since many issues regarding diagnosis and counseling apply to the group as a whole, this allows a common approach to clinical management. However, the substantial genetic contribution to common diseases, i.e. the delineation of genetic variants in the complement pathway as contributors to AMD, and normal quantitative traits (corneal thickness, optic nerve size) underlines the observation that molecular genetic discoveries are not limited to Mendelian disease.

The study of inherited ocular disease represents one of the successes of modern molecular genetics, from the description of linkage of xlRP⁷ to the identification of the first adRP gene encoding rhodopsin.⁸ The Human Genome Project has accelerated the understanding of the molecular basis of human genetic disease. Now, over 200 gene loci and 150 genes have been described underlying human monogenic retinal disorders, implying a level of complexity unsuspected 20 years ago (http://www.sph.uth.tmc.edu/retnet/).

Mendelian inheritance

The human genome is divided among 46 (23 pairs, humans are diploid) physically distinct chromosomes. There are 22 pairs of autosomes plus two sex chromosomes: in the female two X chromosomes, in the male an X and a Y. Human chromosomes vary widely in size and the genes mutated in monogenic ocular disorders are scattered randomly.

Autosomal dominant inheritance (Fig. 10.1)

Autosomal dominant (AD) conditions are caused by mutations in genes on chromosomes 1–22. An affected individual carries one normal and one mutated copy of the gene (i.e. the condition is expressed in the heterozygous state). In most families with AD conditions there are multiple generations with both males and females affected to a similar degree, and male to male transition. Affected individuals have a 1 in 2 chance of passing a mutated gene to each offspring, regardless of sex. The risk to offspring of unaffected individuals is that of the general population, provided that unaffected individuals are certain not to carry the mutated copy of the gene.

Fig. 10.1 Pedigree construction illustrating autosomal dominant inheritance.

Expressivity

Within one family, individuals affected by a single gene disorder carry the same genetic fault. However, the manifestations of that condition may vary widely. The condition or more properly the, mutant allele is said to demonstrate variable expressivity. Examples include Marfan’s syndrome, neurofibromatosis type I, and oculocutaneous albinism whose ocular and extraocular manifestations vary widely amongst those who carry a mutation. Phenoptypic severity in one individual may have little or no implication for predicting disease severity for siblings or offspring. This leads to uncertainty around interpreting predictive or prenatal genetic testing and means that examining the parents of affected children is essential in determining the presence of mild features and predicting dominant (50%) risks for future offspring.

Penetrance

For some AD conditions, the probability of gene carriers developing symptoms is not 100% (i.e. the mutation shows reduced penetrance). Therefore, for many conditions (e.g. forms of AD retinitis pigmentosa (adRP), coloboma, or congenital cataract), gene carriers may not have signs of the condition but have an identical risk for their offspring as those who do. This is another reason for examining the parents of a child with, for example, coloboma or anterior segment dysgenesis. The availability of genetic testing is helpful in providing accurate risks.

New mutations

Dominant conditions may arise de novo. In this case, there is no family history and the condition has arisen as the result of a copying error from one parent’s DNA. This is seen in many cases of aniridia or retinoblastoma. In such cases, the recurrence risks for future siblings are much lower than 50%. The figure will not be zero due to the risk of gonadal mosaicism (i.e. one parent carrying the mutation in a proportion of his/her sperm or eggs).

The exact nature of a de novo mutation is difficult to predict – for cases of sporadic aniridia, a deletion can remove other neighboring genes. This is seen in WAGR syndrome where a deletion causes Wilms’ tumor, aniridia, genitourinary abnormalities, and intellectual retardation.^9–11 This is termed a contiguous gene syndrome. It is for this reason that patients with sporadic aniridia require either renal ultrasound screening or molecular evidence that the Wilms’ tumor gene, WT1, is unaffected by the new mutation (Fig. 10.2).

Fig. 10.2 Pedigree construction illustrating autosomal recessive inheritance in the presence of consanguinity.

Once a new AD mutation has arisen, an affected individual has a 50% risk for their own offspring. Examples of these conditions include rare forms of Leber’s congenital amaurosis (caused by mutations of the CRX gene) and retinoblastoma (caused by mutations in the RB1 gene). As RB1 mutation may also show reduced penetrance, the presence of unaffected parents could either mean that an affected child carries a de novo mutation or that the parent carries a mutation which exhibits reduced penetrance. Genetic testing may help to identify those carrying disease-causing genes and define risks to family members.

Autosomal recessive inheritance (Fig. 10.3)

For autosomal recessive (AR) conditions, affected individuals carry faults on both copies of a given gene (either homozygous where both copies carry the same mutation, or compound heterozygotes where each copy carries a different pathogenic gene fault). Conditions inherited in this fashion include oculocutaneous albinism, autosomal recessive congenital cataract, most forms of Leber’s congenital amaurosis, and achromatopsia.

Fig. 10.3 Pedigree construction illustrating x-linked recessive inheritance.

Parents carry one normal and one mutant gene copy but have normal vision as the normal copy is sufficient to produce normal function. For two carrier parents, the risk of having an affected child is . Unaffected children have a risk of being carriers.

Recessive conditions can appear as “sporadic” in a family where all parents and siblings are healthy, particularly in smaller families. In the absence of genetic testing, predicting AR inheritance is difficult and may be inferred on the basis of lack of vertical transmission (unaffected parents) and exclusion of X-linked inheritance.

Calculating carrier frequencies in the general population is complex. For inherited eye conditions, where one condition may be caused by many different genes (e.g. retinal dystrophy), accurately predicting the frequency of any one of those genes in a given population is often not possible. For Stargardt’s disease with an estimated disease frequency of 1 in 10 000¹² and a carrier frequency of 1 in 50, the risk to the offspring of an affected individual and their children is low (~1% and 0.65%, respectively).

Cousin marriages increase the likelihood that spouses carry an identical gene change. In many ethnic groups, cousin marriages are an important part of family culture. Discussion of the increased risks to future children, if close cousins marry, must be done with sensitivity and appreciation of the cultural issues.

X-linked inheritance (Fig. 10.4)

“Sex linked” conditions are caused by mutations in X chromosome genes. As males have only one X chromosome, such a genetic mutation will be manifest. Heterozygous females will be “carriers” and either unaffected or more mildly affected. The essential features of X-linked inheritance are the presence of affected males (of greater severity than females) and lack of father to son transmission. Females of affected males are obligate carriers. Female carriers have a 50% chance of passing on the mutation, with each son having a 50% chance of being affected, and half their daughters being “carriers.” X-linked conditions include Nance-Horan syndrome, Norrie’s disease, retinitis pigmentosa (xLRP), congenital stationary night blindness, choroideremia, and retinoschisis.

Fig. 10.4 Aniridia caused by deletion of chromosome 11.

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