Terminology: Hereditary, Genetic, Familial, Congenital
Hereditary indicates that a disease or trait under consideration results directly from an individual’s particular genetic composition (or genome) and that it can be passed from one generation to another. Genetic denotes that the disorder is caused by a defect of genes, whether acquired or inherited. In some instances, such as mutations in genes related to ocular melanoma, the disease is clearly genetic, but it is not passed to subsequent generations and is therefore not hereditary. Thus, the terms hereditary and genetic are not synonymous but are sometimes used to convey similar concepts. Both hereditary and genetic disorders may be congenital or develop later in life.
A condition is familial if it occurs in more than one member of a family. It may, of course, be hereditary but need not be. A familial disorder can be caused by common exposure to infectious agents (eg, adenoviral conjunctivitis), excess food intake (eg, obesity), or environmental agents, such as cigarette smoke. Genetic factors, however, may contribute to the effects of exposure to these environmental factors and may cloud the picture.
The term congenital refers to characteristics present at birth. These characteristics may be hereditary or familial, or they may occur as an isolated event, often as the result of an infection (eg, rubella, toxoplasmosis, or cytomegalovirus) or a toxic agent (eg, as in thalidomide embryopathy or fetal alcohol syndrome). The presence of such characteristics at birth or shortly after (in the first weeks of life) is the defining factor. Pediatric ophthalmology literature has traditionally used the terms congenital nystagmus, congenital esotropia, congenital glaucoma, and congenital cataract; however, in many cases, these disorders are not present at birth and would be more accurately referred to as infantile.
Heritability refers to the proportion of phenotypic variation in a population that is attributable to genetic variation among individuals. Estimation of heritability aims to answer the “nature versus nurture” debate and to allow researchers to pursue genetic and/or environmental determinants of disease, although most cases involve a combination of the 2 determinants. Heritability studies compare the phenotypic similarity of genetically closely related individuals with that of less closely related individuals. The best example of this type of study is a comparison of the correlation of identical twins (monozygotic twins, who share 100% of their DNA sequence) with that of nonidentical twins (dizygotic twins, who share 50% of their DNA sequence). With both twins sharing the same age and similar intrauterine and early childhood environments, most of the variation is thought to be due to genetic factors. An example of a twin study concerning the highly heritable trait of central corneal thickness is shown in Figure 6-3.
A condition known to be genetic and hereditary (eg, RP) may appear in only 1 individual of a family. Such an individual is said to have a simplex, or isolated, form of a genetic disease. A genetically determined trait may be isolated in the pedigree for several reasons:
The pedigree is small.
The full expression of the disease has not been sought or has not manifested in other relatives.
The disorder represents a new genetic mutation or chromosomal change.
The disorder is recessive, and the investigation to determine whether the parents are carriers has been inadequate.
There is nonpaternity.
Clinically similar disorders may be inherited in several different ways. For example, RP can occur from an autosomal dominant, autosomal recessive, X-linked recessive, or mitochondrial mutation. These various genetic forms represent distinct gene defects with different alterations in gene structure and various biochemical pathogeneses, each of which has similar clinical phenotypic expressions. Clarification of genetic heterogeneity is important, because only with the proper diagnosis and correct identification of the inheritance pattern can appropriate genetic counseling and prognosis be offered.
Figure 6-3 Comparison of correlation level for central corneal thickness in a set of monozygotic (MZ) twins with that of a set of dizygotic (DZ) twins. Left, Comparison for the MZ twins (correlation, 0.95). Right, Comparison for the DZ twins (correlation, 0.52). The difference in the correlation levels of the 2 sets of twins allows for calculation of the heritability of central corneal thickness, which in this example is 95%.
(Courtesy of David A. Mackey, MD.)
Some genetic disorders originally thought to be a single and unique entity are found, on close scrutiny, to be two or more fundamentally distinct entities. Further clarification of the inheritance pattern or biochemical analysis permits separation of initially similar disorders. Such has been the case for Marfan syndrome and homocystinuria. Patients with these disorders tend to be tall and thin, with long arms, legs, fingers, and toes; they also have ectopia lentis. However, the presence of dominant inheritance, aortic aneurysms, and valvular heart disease in Marfan syndrome distinguishes it from the recessive pattern and thromboembolic disease of homocystinuria.
Genetic heterogeneity is a general term that applies to the phenotypic similarity that may be produced by two or more fundamentally distinct genetic entities; this term implies that the genes are nonallelic. Leber congenital amaurosis, which has more than 14 causative genes, is a good example (Fig 6-4). Once the location on a chromosome is determined for a particular disease gene, and the gene’s molecular structure is identified, most examples of genetic heterogeneity cease to be a problem for diagnosis or classification. However, clinical, allelic, and locus heterogeneity can remain perplexing issues. For example, mutations of the Norrie disease gene, NDP, usually result in the typical phenotype of pseudoglioma from exudative retinal detachments, but some NDP mutations have been associated with X-linked exudative vitreoretinopathy without any systemic associations.
Sanfilippo PG, Hewitt AW, Hammond CJ, Mackey DA. The heritability of ocular traits. Surv Ophthalmol. 2010;55(6):561–583.
Figure 6-4 Prevalence of the 14 causative genes known in 2008 for cases of Leber congenital amaurosis (led by CEP290 in approximately 15% of cases). Mutations for approximately 30% of cases remain to be identified.
(Reproduced with permission from den Hollander AI, Roepman R, Koenekoop RK, Cremers FP. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res. 2008;27(4):391–419.)
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.