Variability is an intrinsic property of human genetic disease that reflects the quantitative and qualitative differences in phenotype among individuals with the “same” mutant allele. Even within a single family with a genetic disease, each affected individual may manifest the disease to a different degree, with different features, or at a different age. For example, there is wide variation in both severity and age at detection of features of myotonic dystrophy (also called Steinert disease), which include motor myotonia, cataracts, gonadal atrophy, and presenile baldness. Even within a single family, the characteristic cataracts may begin to affect vision at any time from the second to the seventh decade of life.
Such variability of clinical manifestation led to the concept of anticipation, the phenomenon of apparently earlier and more severe onset of a disease in successive generations within a family. Before 1990, most geneticists thought that anticipation was not a biological phenomenon but rather an artifact of ascertainment. With the relatively recent discovery of triplet or trinucleotide tandem-repeat expansion diseases, anticipation has been shown to reflect the increased length of trinucleotide tandem repeats from one generation to the next. Anticipation occurs in autosomal dominant disorders. Myotonic dystrophy, fragile X syndrome, Huntington disease, and Kennedy disease (a form of spinobulbar muscular atrophy) are some of the diseases whose discovery contributed to the rejuvenation of the concept of anticipation.
Some human variability may result from the intrinsic differences in the genetic background of every human being. Other recognizable or presumptive influences on the variable intra- or interfamilial phenotype of the same gene include the following factors:
sex influences or limitations
maternal factors, such as intrauterine environment and even cytoplasmic (eg, mitochondrial) inheritance factors
genetic heterogeneity, including both isoalleles and genocopies
gene alterations induced either by position effects with other genes or by somatic mutations
epigenetic factors, methylation, and histone formation
Obviously, nongenetic factors (eg, diet, temperature, and drugs) may affect gene expression, either as phenocopies or through ecologic par ameters.
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.