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Ophthalmic Genetics

James J. Augsburger, MD, and Zélia M. Corrêa, MD, PhD

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

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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 inheritance pattern is autosomal dominant.

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The characteristic features of autosomal recessive inheritance are as follows:

1.The genetic abnormality is usually a small mutation in a single gene or small number of adjacent genes on one of the somatic chromosomes and is expressed only when an individual has inherited it from both parents.

2.The condition due to the genetic mutation is usually present in a single generation (unless there is a high level of consanguinity in the mating pool).

3.On average, one in four of the children of parents who both carry the mutated gene manifests the condition and two in four are carriers.

4.Males and females are affected equally.

Ophthalmic conditions exhibiting autosomal recessive inheritance include the following:

1.Retinitis pigmentosa (some forms)

2.Gyrate atrophy

3.Xeroderma pigmentosum

The characteristic features of X-linked recessive inheritance are as follows:

1.The genetic abnormality is usually a small mutation in a single gene or small number of adjacent genes on the sex (X) chromosome. This gene is expressed only when it is not balanced by a normal X chromosome inherited from the unaffected parent.

2.The genetic mutation and the associated condition are present in multiple consecutive generations.

3.The mutated X chromosome is transmitted, on average, to half of the children of both affected males and carrier females.

4.Only males are affected by the complete condition, but female carriers may have a limited manifestation.

Ophthalmic conditions exhibiting X-linked recessive inheritance include the following:

1.X-linked retinoschisis

2.Ocular albinism

3.Retinitis pigmentosa (some forms)

4.Norrie’s disease

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5. Choroideremia (most cases)

The characteristic features of mitochondrial inheritance are as follows:

1.The genetic abnormality is a mutation in a single or small group of adjacent genes of mitochondrial DNA, such as the point mutations of the cytoplasmic mitochondria that cause Leber’s hereditary optic neuropathy.

2.The genetic abnormality is transmitted from a carrier mother to all her children.

3.Only carrier mothers transmit the condition to their children.

4.Both males and females are affected.

Examples of ophthalmic disorders transmitted by mitochondrial inheritance are as follows:

1.Leber’s hereditary optic neuropathy

2.Kearns-Sayre syndrome: Principal ophthalmic features are chronic progressive external ophthalmoplegia and pigmentary retinopathy

Some ophthalmic diseases, including age-related macular degeneration and primary open-angle glaucoma, have a polygenic and multifactorial pattern of inheritance, occurring in family members substantially more frequently than expected on the basis of chance alone but without a simple pattern of inheritance. Mutations of multiple different genes have been associated with these conditions, and interactions between them and environmental conditions affect the characteristics of the conditions, such as age at clinical onset, severity at initial detection, rapidity of progression, and ultimate outcome.

Chromosomal Abnormalities

Some ophthalmic conditions are due to a genetic defect but are rarely transmitted through more than one generation. In most of them, there is a major or complete loss or duplication of one or more chromosomes involving numerous genes. Due to absence of half the normal complement of genes associated with a particular chromosome in cases with complete chromosomal deletions and to the presence of 50% more than the normal complement of genes associated with a particular chromosome in cases with complete chromosomal duplications, affected individuals characteristically have multiple morphological abnormalities that frequently prompt chromosomal analysis during infancy or early childhood. Affected individuals frequently are sterile or unsuccessful in reproducing or do

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not reach reproductive age, thus accounting for the lack of multigenerational transmission. In most cases, the abnormal complement of chromosomes can be identified by karyotyping. The main chromosomal disorders and their common ophthalmic manifestations are as follows:

1.Trisomy syndromes

•Trisomy 13 (Patau’s syndrome): Microphthalmia, uveal colobomas, congenital cataract

•Trisomy 18 (Edward’s syndrome): Hypertelorism, hypoplastic supraorbital ridges, eyelid anomalies

•Trisomy 21 (Down’s syndrome): Epicanthal folds, iris hypoplasia, keratoconus

•XXY trisomy (Klinefelter’s syndrome): Epicanthal folds, hypertelorism, upward slant of palpebral fissures

2.Monosomy syndrome

•Monosomy X (Turner’s syndrome): Congenital ptosis, strabismus, cataract

3.Partial chromosomal deletion or duplication syndromes

•Chromosome 13q deletion syndrome: Hypertelorism, epicanthal folds, retinoblastoma

•Chromosome 11p deletion syndrome: Congenital aniridia

PRINCIPAL USES OF GENETIC DIAGNOSIS IN OPHTHALMOLOGY

The principal uses of ophthalmic genetic diagnosis are as follows:

1.Identification of clinically unaffected carriers of a familial disease, for the purposes of familial genetic counseling and risk prognostication

2.Identification of individuals in a family who are predisposed genetically to develop a familial disease but have not yet done so (for the purpose of justifying periodic screening evaluations)

In practice, the clinician first must recognize a familial inheritance pattern in more than one generation or branch of a family or diagnose in one or more

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members of the same generation of a family an ophthalmic condition that is known to be transmitted genetically in at least some families. In the former situation, a genetic counselor:

1.Investigates the family pedigree, identifies the likely inheritance pattern of the disease, and suggests and arranges for genetic testing of the family.

2.Determines which family members are affected or predisposed to develop the disease and/or determines unaffected carriers who can transmit the disease to their offspring, and advises the family as a whole, affected individuals, and carriers about the genetic findings and their implications.

In diseases for which effective treatment is available if it is detected when limited in extent, genetic differentiation between individuals who are and those who are not predisposed to develop the disease assists targeting of screening programs. For instance, in familial retinoblastoma that is potentially fatal, identification of at-risk individuals justifies frequent ophthalmic examinations under anesthesia to detect newly emerging retinal tumors in infants at risk, and such examinations should be avoided in infants shown not to be at risk. Familial genetic testing allows detection of carrier status of clinically unaffected individuals who have the potential to pass the disease on to their offspring. Such information can be used in family planning or to justify early genetic and clinical evaluation of any future offspring for evidence of the disease or genetic susceptibility to it.

For diagnosis in one or more members of the same generation of a family of an ophthalmic condition known to be transmitted genetically in at least some families and for which genetic testing is currently available (eg, Norrie’s disease and Leber’s hereditary optic neuropathy), testing of the affected individual(s) and their parents and siblings can be performed to determine the presence of the genetic abnormality. If a relevant genetic abnormality is identified in an affected family member but not in any other family members, it is likely to be due to a new mutation. In contrast, if neither the affected individual nor any first-degree relative has a relevant genetic abnormality, either the clinical diagnosis is incorrect or an unknown genetic abnormality is responsible.

Family pedigrees can be used to support or, in some cases, refute clinical diagnosis of a condition transmitted in at least some families according to a particular genetic pattern. For example, in ophthalmic conditions with maternal inheritance via mitochondrial DNA (eg, Leber’s hereditary optic neuropathy, Kearns-Sayre syndrome), affected mothers transmit the disease to their offspring of either sex, but affected fathers do not transmit the disease. Thus, if a child and

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father are affected, the clinical diagnosis is unlikely to be correct. Similarly, if the inheritance is X-linked recessive (eg, X-linked retinoschisis), the mother of an affected individual is likely to be an unaffected carrier; 50% of sons of a carrier mother manifest the condition; 50% of daughters of a carrier mother are carriers; sons of affected males are unaffected; and daughters of affected males are carriers. Thus, if a son and father are affected, the clinical diagnosis is unlikely to be correct.

GENETIC PROGNOSTICATION

Genetic prognostication refers to the use of genetic information to predict a patient’s prognosis.

Retinitis pigmentosa is caused by a variety of mutations with several patterns of inheritance (autosomal dominant, autosomal recessive, or X-linked recessive). Individuals from a particular family, thus having the same genotype, are likely to have the same clinical manifestations (phenotype) (eg, age when visual symptoms are first recognized, severity of visual field loss at initial detection, rate of progression following initial symptoms, and ultimate level of visual loss), whereas individuals from different families will tend to have different clinical manifestations. Such genotype-phenotype correlations have been defined for several genetic subtypes of retinitis pigmentosa. Similarly in von Hippel-Lindau disease, which has an autosomal dominant pattern of inheritance, there are genetic subgroups with substantially different risk of developing renal cell carcinoma.

Many cases of retinoblastoma occur as a familial disease with an autosomal dominant inheritance pattern, but the defect in the retinoblastoma gene in the tumor cells does not seem to influence disease severity or ultimate survival outcome. In contrast, although there is not a strong familial tendency, most primary uveal melanomas that ultimately metastasize have deletion of one chromosome 3 (monosomy 3) or a characteristic gene expression profile (class 2) within the tumor cells. If either abnormality is detected, such as in a biopsy, enucleation, or resection specimen, the patient is at high risk of metastatic disease and should be encouraged to participate in an adjuvant therapy clinical trial to identify interventions that prevent or delay the onset of metastasis (see www.clinicaltrials.gov).

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GENE THERAPY

Gene therapy is the attempted elimination or amelioration of disease, due to loss (deletion) or functional inactivation of one or a few adjacent genes, by inserting, incorporating, and activating replacement segments of DNA corresponding to the deleted or nonfunctional gene, so as to achieve normal gene function. In ophthalmology, only a few trials are in progress (eg, retinitis pigmentosa, Leber’s hereditary optic neuropathy, and some corneal disease) but with good safety profile of viral vector gene transfer and as-yet limited recovery of function (see www.clinicaltrials.gov).

REFERENCES

Allen KF et al: Genetics of primary inherited disorders of the optic nerve: Clinical applications. Cold Spring Harb Perspect Med 2015;5:a017277. [PMID: 26134840]

Bainbridge JWB et al: Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med 2015;372:1887. [PMID: 25938638]

Benjaminy S et al: Communicating the promise for ocular gene therapies: Challenges and recommendations. Am J Ophthalmol 2015;160:408. [PMID: 26032192]

Branham K et al: Providing comprehensive genetic-based ophthalmic care. Clin Genet 2013;84:183. [PMID: 23662791]

Chan S et al: Advances in the genetics of eye diseases. Curr Opin Pediatr 2013;25:645. [PMID: 24126856]

Comander J et al: Visual function in carriers of X-linked retinitis pigmentosa. Ophthalmology 2015;122:1899. [PMID: 26143542]

Daiger SP et al: Genes and mutations causing retinitis pigmentosa. Clin Genet 2013;84:132. [PMID: 23701314]

Dalkara D et al: Let there be light: Gene and cell therapy for blindness. Hum Gene Ther 2016;27:134. [PMID: 26751519]

Edwards TL et al: Visual acuity after retinal gene therapy for choroideremia.

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N Engl J Med 2016;374:1996. [PMID: 27120491]

Findeis-Hosey JJ et al: Von Hippel-Lindau disease. J Pediatr Genet 2016;5:116. [PMID: 27617152]

Helgadottir H et al: The genetics of uveal melanoma: Current insights. Appl Clin Genet 2016;9:147. [PMID: 27660484]

Jacobson SG et al: Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med 2015;372:1920. [PMID: 25936984]

Kaliki S et al: Uveal melanoma: Estimating prognosis. Indian J Ophthalmol 2015;63:93. [PMID: 25827538]

Kersten HM et al: Ophthalmic manifestations of inherited neurodegenerative disorders. Nat Rev Neurol 2014;10:349. [PMID: 24840976]

MacLaren RE et al: Retinal gene therapy in patients with choroideremia: Initial findings from a phase 1/2 clinical trial. Lancet 2014;383:1129. [PMID: 24439297]

Meyerson C et al: Leber hereditary optic neuropathy: Current perspectives. Clin Ophthalmol 2015;9:1165. [PMID: 26170609]

Nash BM et al: Retinal dystrophies, genomic applications in diagnosis and prospects for therapy. Transl Pediatr 2015;4:139. [PMID: 26835369]

Nichols EE et al: Tumor characteristics, genetics, management, and the risk of metastasis in uveal melanoma. Semin Ophthalmol 2016;31:304. [PMID: 27128983]

Riaz M et al: Genetics in retinal diseases. Dev Ophthalmol 2016;55:57. [PMID: 26501365]

Scanga HL et al: Genetics and ocular disorders: A focused review. Pediatr Clin North Am 2014;61:555. [PMID: 24852152]

Soliman SE et al: Knowledge of genetics in familial retinoblastoma. Ophthalmic Genet 2016 Jul 18:1. [Epub ahead of print] [PMID: 27427836]

Sorrentino FS et al: A challenge to the striking genotypic heterogeneity of retinitis pigmentosa: A better understanding of the pathophysiology using the newest genetic strategies. Eye (Lond) 2016;30:1542. [PMID: 27564722]

Wiley LA et al: Stem cells as tools for studying the genetics of inherited retinal degenerations. Cold Spring Harb Perspect Med 2014;5:a017160. [PMID: 25502747]

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Zinkernagel MS et al: Recent advances and future prospects in choroideremia. Clin Ophthalmol 2015;9:2195. [PMID: 26648685]

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