DNA is made up of four nucleotides each containing one of four bases: adenine (A), thymine (T), cytosine (C), and guanine (G). DNA is read three nucleotides at a time: each triplet, known as a codon, corresponds to a specific amino acid at a specific position in the translated protein. Exons are made of series of codons of varying length. Some codons instruct for the process of translation to stop, whereas other codons instruct for the process to begin.
Sequence changes in a gene may or may not be pathogenic. The majority of changes are polymorphic variants, which cause the natural variation in humanity without causing disease. A mutation is a sequence change that results in disease or dysfunction or may be incompatible with life. In some cases, mutations can be tolerated if another gene compensates for the defective gene’s tasks.
Mutations may affect translation and transcription in different ways (Fig. 2.2). A nonsense mutation occurs when a nucleotide substitution converts a codon from one that encodes for an amino acid to one that creates a stop in the transcription process, which results in premature termination of translation and a truncated protein product. A DNA change that leads to a substitution of one amino acid for another is called a missense mutation, which produces a protein with same number of amino acids, but the function or structure of the resulting protein could be altered. A frameshift mutation occurs when there is a deletion or insertion of a base or bases into the gene sequence that shifts the sequence reading frame: for example, the insertion of a G that would change the sequence ACTGAACTT to ACGTGAACTT would cause the reading of the original three triplets (ACT, GAA, CTT) to shift to the right (ACG, TGA, ACT) causing a jumbled amino acid read, likely resulting in a nonfunctional protein.
Genes have many functions. Some code for structural proteins such as collagen and fibrillin. Others code for enzymes. Some genes regulate the activity of other genes. These regulators are called transcription factors or developmental genes. Each gene has a promoter, which is DNA that is usually located upstream of a gene, and it controls or regulates the transcription of that gene. Transcription factors bind to the promoter of genes to initiate or to control DNA transcription.9
Humans have approximately 25,000 to 30,000 genes distributed on 23 chromosomes. Chromosomes 1 to 22 are called autosomes. Every individual has two copies of each chromosome: one from the mother and one from the father. Therefore, each human has two copies of each gene, each of which is referred to as an allele. In addition, each female has two X chromosomes, and males have one X and one Y chromosome. A person with an identical mutation on each allele is said to be homozygous. If the mutation occurs on only one allele, the person is heterozygous. In the case of a male who has a mutation in a gene on his sole X chromosome, he is said to be hemizygous. If there are mutations in both copies of the gene but the mutations (of the same gene) are different, the person is a compound heterozygote.
Each chromosome has a short arm (p) and a long arm (q). Abnormalities of chromosomes can be numerical or structural. Chromosomes have structural features that can be used to locate aberrations or genes. The centromere is the (central) constricted area of a chromosome, which is an important structure during cell mitosis and meiosis. Mitosis is part of the process of natural somatic cell division by which the chromosomes duplicate and divide into two daughter cells such that each resulting offspring cell contains 46 (23 pairs) of chromosomes. Meiosis is the process by which chromosomes undergo duplication and divisions during gamete formation to produce sperm and egg cells, each of which contains only 23 chromosomes. Telomeres are the ends of each chromosome. The subtelomeric regions, just centromeric to the telomere, tend to be gene rich. Chromosomal banding techniques make use of dyes to identify chromosomal regions along the length of the chromosome, dividing the chromosome into sections, subsections, and subsubsections. A specific nomenclature is used to describe these regions: 2p13.4 specifies the short arm of chromosome 2, section 1, subsection 3, subsubsection 4. The number increases as one moves away from the centromere toward the telomere. Bands are not genes, and the section system does not correspond to banding, as different dyes create different bands. Each band may contain many genes. The International System for Cytogenetic Nomenclature is generally used for the mapping system of chromosomes.10 Structural changes may be constitutional (occurring from conception) or acquired (usually associated with neoplastic diseases). Structural abnormalities of chromosomes include translocations, inversions, rings, and other variations that may disrupt gene function (Figs. 2.3–2.5). A balanced translocation means that material from one chromosome is found situated on another chromosome but no chromosomal material is lost or damaged. The patient is phenotypically normal, but his or her offspring may inherit various combinations of unbalanced chromosomal material as a result. Rings, inversions, translocations, and other aberrations may also result in damage to specific genes at the breakpoints of the chromosomal change or copy number variations – gains or losses of DNA on a chromosome.
Genetic disease can therefore be caused by mutations in single genes or by chromosomal aberrations involving more than one gene. There are many other mechanisms of genetic disease that are beyond the scope of this chapter. For example, some genes are transcribed into RNA but never translated into protein. These microRNAs (miRNAs) serve regulatory functions.11 They are transcribed in the nucleus, processed, and transported to cytoplasm, where they affect mRNA translation of other gene products. When abnormal, microRNAs can play important roles in organ maldevelopment such as in anophthalmia,12 tumorigenesis,13 and also glaucoma and cataract.
Epidemiology
Genetic disorders account for 14% to 44% of childhood blindness worldwide and 10% to 20% in the United States.14 Chromosomal abnormalities account for approximately 6% of birth defects in industrialized countries.3 Trisomy 21, for example, is estimated to be 1 in 1000 live births worldwide.15 It is estimated that more than 10,000 monogenic diseases could occur in human beings.16 The prevalence of monogenic human diseases is approximately 1% worldwide.16 In industrialized countries, single gene defects may be responsible for as many as 7.5% of all birth defects.3 In some low-income and middle-income countries, consanguinity rates may be as high as 20% to 50%, leading to an increased incidence of autosomal recessive disorders.17 Multifactorial disorders, which involve both genetic and environmental influences, account for 20% to 30% of all birth defects.3
In the case of Mendelian diseases, 58% involve more than one organ or system, and the eye is one of the most frequently involved.18 These diseases have profound impact on longevity and function. Of affected individuals, only 42.5% have a normal lifespan, and 23.7% die before they reach the reproductive age. Those with Mendelian diseases involving the eye have relatively longer longevity, but survivors carry lifelong vision disabilities. In a Spanish study analyzing more than 1 million births, anophthalmia/microphthalmia, congenital cataract, and coloboma were the most common congenital eye malformations.19 The authors of this study found that 60%, 15%, 10%, and 5.83% of total syndromes identified among infants with eye malformations had chromosomal, autosomal recessive, environmental, and autosomal dominant etiologies, respectively. A majority of patients with eye malformations also had other systemic diseases: limb anomalies (59.3%) and auricular/facial disorders (47.1%), central nervous system disorders (42.5%), and disorders of the musculoskeletal system, excluding limbs (42.2%).
Pathogenesis and Etiology
Common Inheritance Patterns of Diseases
Single gene disorders follow the classic Mendelian patterns of inheritance: autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant. Table 2.1 gives examples of disorders with various inheritance patterns, which have oculoplastics manifestations.
Table 2.1
Examples of Genetic Disorders with Oculoplastic Manifestations
| Inheritance Pattern | Examples of Oculoplastic Syndromes | Mutated Gene(s) |
| Autosomal dominant | Apert syndrome | FGFR2 (10q26) |
| Autosomal dominant | Oculopharyngeal dystrophy | PABPN1 (14q11.2) |
| Autosomal recessive | Fraser syndrome | FRAS1 (4q21.21) FREM2 (13q13.3) GRIP1 (12q14.3) |
| Autosomal recessive | Achalasia-Addisonianism-Alacrimia syndrome | AAAS (12q13.13) |
| X-linked recessive | Lenz microphthalmia syndrome | BCOR (Xp11.4) |
| X-linked dominant | Goltz syndrome | PORCN (Xp11.23) |
| Mitochondrial | Chronic progressive external ophthalmoplegia (CPEO) | Mitochondrial genome deletion(s) |
| Chromosomal aberration | Down syndrome | Trisomy 21 |
| Chromosomal aberration | Turner syndrome | Female monosomy X (XO) |
When a disease-producing gene is located on an autosome (chromosomes 1–22) and only one copy of the gene is mutated, the disease is said to be autosomal dominant. This may be inherited from either parent or may start as a de novo (spontaneous) mutation in the patient. An affected patient, regardless of gender, has a 50% risk of transmitting the mutation to each child, regardless of the patient’s or the child’s gender. Autosomal dominant disease can be subject to incomplete penetrance and variable expressivity. Penetrance refers to any clinically evident signs of a disorder, a phenotypic expression. If an individual has the mutation but no clinical manifestations of the disorder, he is said to be nonpenetrant. Variable expressivity refers to the range of phenotypic traits that occur in different patients with the same mutation, varying from mild to severe, or even manifesting different malformations. For example, in the same family, one individual with autosomal dominant neurofibromatosis type I resulting from a mutation in the NF1 gene may have a severe plexiform neurofibroma of the lids or orbit, whereas another may have no plexiform neurofibroma but develop an optic nerve glioma (see Chapter 18).
Examples of autosomal dominant disease affecting the orbits include multiple craniosynostosis syndromes such as Apert syndrome.20 Associated ophthalmic findings include refractive error, strabismus often caused by ectopic, malformed or absent extraocular muscles; ptosis; exophthalmos from shallow orbits, sometimes resulting in exposure keratopathy; papilledema; and optic atrophy.20,21 Apert syndrome is caused by mutation of the fibroblast growth-factor receptor 2 gene (FGFR2) located at chromosome 10q26.22 The gene is important in the regulation of cranial suture fusion. Crouzon and Pfeiffer syndromes can also result from a variety of different FGFR2 point mutations.23,24 This is an example of phenotypic heterogeneity, where different mutations in the same gene may result in different disorders. Congenital cranial dysinnervation disorders (e.g., Moebius syndrome, congenital fibrosis of the extraocular muscles, Duane syndrome), Treacher Collins syndrome and aplasia of the lacrimal glands are also autosomal dominant disorders.
An autosomal recessive disease occurs when two mutated copies of an autosomal gene are required to produce an abnormal phenotype. If both parents are carriers (each with a mutation on only one copy of the gene and no disease state), each of their children will have a 25% risk of having the disease (two copies of the flawed gene), a 50% risk of carrying the gene without disease manifestations (one copy of the healthy gene and one copy of the flawed gene), and a 25% chance to inherit two normal copies. An affected individual must procreate with a carrier or another affected individual to produce an affected child. In general, the risk of unknowingly reproducing with a carrier is less than 3%. The risk of autosomal recessive disease in offspring is increased if one conceives a child with a relative or member of an ethnically homogeneous group. Affected individuals may have the same mutation on each copy of their gene (homozygous mutations) or have a different mutation on each copy (compound heterozygous mutations). Phenotype reflects which mutations are present. Examples of autosomal recessive disorders with oculoplastic manifestations include oculocutaneous albinism, Achalasia-Addisonianism-Alacrimia syndrome, and Fraser syndrome.
X-linked disorders involve genes on the X chromosome. Examples of X-linked recessive disorders that have oculoplastic implications include dyskeratosis congenita, Lenz microphthalmia syndrome, and a form of microphthalmia with coloboma. In females, X-linked recessive disorders require mutations in both gene copies to cause disease, similar to autosomal recessive disorders. As males only have one X chromosome, a mutation on their single copy of the gene will cause disease. If a father has the disease and mother is normal, all of their sons will be normal, as the father must pass his Y chromosome to create a son. All of their daughters will be carriers as the father must use his single X chromosome, with its mutated gene, to create a daughter. Hence, there is no male-to-male transmission. If the mother is a carrier, she could either have no manifestation or could have varying degrees of signs as a result of Lyonization. Lyonization is a process whereby all females inactivate one of their X chromosomes in each of their cells. For a female carrier of X-linked disorders, if the normal X chromosome is inactivated, only the “carrier” cells will manifest the sequelae of that mutation. In general, inactivation is random and the number of cells using the mutated X versus the normal X is fairly equal. This results in few or no detectable clinical manifestations of the disorder. If inactivation is skewed such that there is an overabundance of cells, locally or more throughout the body, expressing the mutated X chromosome instead of the normal X, then clinical manifestations of the disease may occur. For example, carriers of X-linked ocular albinism could have a “mud-splattered” fundus, in which melanotic patches represent retinal pigmented epithelium (RPE) cells expressing the normal X chromosome and amelanotic patches represent RPE cells expressing the abnormal X chromosome.25 Carriers may also have hypopigmented macules on their skin representing a clone of cells expressing the X chromosome with the mutated OA1 gene.
When mutation in only one copy of an X chromosome gene is enough to cause the disease in a female, it is considered X-linked dominant disease. As males only have one X chromosome, X-linked dominant disorders are usually lethal or more severe. An affected mother will have a 50% chance with each pregnancy of having an affected child. Miscarriages of male fetuses are an indicator of a possible X-linked dominant disorder. Goltz syndrome (focal dermal hypoplasia MIM 305600) is an X-linked dominant condition caused by mutations in the PORCN gene located at Xp11.23. The disease, also known as focal dermal hypoplasia, is a multisystem disorder characterized by skin manifestations, limb malformations, ocular abnormalities, and craniofacial findings. Ocular findings may include anophthalmia or microphthalmia, iris and chorioretinal coloboma, and lacrimal duct abnormalities.26 Other examples of X-linked dominant conditions are Aicardi syndrome and incontinentia pigmenti.
Other Genetic Patterns
Chromosomal Aberrations
All aberrations of chromosome number, whether partial or complete, are known as aneuploidy (the opposite of euploidy). Most common among the aneuploidy disorders are duplications. Duplication of all, or part, of a chromosome is called a trisomy. Most familiar in this category is Trisomy 21, Down syndrome (Fig. 2.6). Indeed, Down syndrome is the most common chromosomal aberration compatible with human life. Chromosomal deletions, whether whole or partial, constitute monosomies. Special cases occur when the alteration involves sex chromosomes. Female monosomy that involves the X chromosome (XO) produces Turner syndrome (short stature, early loss of ovarian function, and infertility). Although most chromosomal aberrations result in prenatal or early postnatal death, hundreds of known variations are compatible with life, many of which show ophthalmic manifestations.27 The very rare condition in which an individual has a complete extra set of chromosomes in every cell (total 69 chromosomes) is called triploidy.
