Genetic analysis of disease has advanced from early approaches of linking sites on chromosomes to a disorder, to genome-wide array analysis (GWAS), which matches genetic variants to a large number of persons with a trait, a method of identifying candidate variations in the genome, to exome sequencing, studying the 1 percent of the genome that is expressed, which is effective in determining the genetic variants associated with rare mendelian disorders that are present in a small number of individuals. A summary of the uses of whole exome sequencing for the diagnosis of rare inherited disorders is given by Yang and colleagues. They were able to identify a disorder in one-quarter of their cohort of 250 patients, including common and rare conditions, some of which were neurologic.
Traditionally, the recognition of the broad categories of genetically determined diseases has rested on their pattern of occurrence in families, segregated according to mendelian inheritance into autosomal dominant, autosomal recessive, and sex-linked types. As mentioned, mutations of nuclear DNA account for the heritable autosomal and sex-linked diseases described in this chapter, and they are remarkably diverse in nature. Some are lethal and are therefore not transmitted to successive generations; others are less harmful and may conform to one of the classic mendelian patterns. The mutation may be large and result in duplication of a major part of a chromosome or even of the entire gene (diploidy or triploidy) or a deletion (haploidy). Other mutations are quite small, involving only a single base pair (“point mutation”). Between these two extremes are deletions or duplications that include a portion of a gene, an entire gene, or contiguous genes, as mentioned above.
The factors conducive to mutations are poorly understood. The parent’s increasing age is important in relation to some mutations; the size, structure, and placement of the gene on the chromosome are important in others. A mutation of the DNA of a germ cell leaves unchanged the somatic phenotype of the individual in whom it occurs, but it may have a devastating effect on the descendants. Conversely, a DNA mutation of a somatic cell affecting only part of the cell population may change the individual harboring it but is not passed on to the descendants. Such an individual, with both normal cells and cells containing the mutant gene, is referred to as a mosaic. Mutations of somatic cells appear to be most pertinent to cancer and aging.
In the monogenic inheritance of all three mendelian patterns, the mutation usually causes an abnormality of a single protein. It may involve an enzyme, peptide hormone, immunoglobulin, collagen, membrane channel, or coagulation factor. Such abnormalities of single genes have been isolated in several hundred diseases, but less is known of their protein products. About one-quarter of these diseases are apparent soon after birth and more than 90 percent by puberty. More than half of them affect more than one organ. Of the 10 in every 1,000 live births with monogenic diseases, 7 are dominant, 2.5 are recessive, and the remainder are sex linked.
Autosomal dominant mutations usually cause manifest disease in heterozygotes, but variations in the size of the gene abnormality can produce any one of several phenotypes. This poses a challenge to the current clinical and pathologic classifications of disease. Moreover, an identical clinical syndrome may be traced to a gene on two different chromosomes. Even more surprising, an estimated 28 percent of all gene loci have polymorphic rather than monomorphic effects—that is, the same mutation has several different phenotypic expressions. Another problem is that of differentiating dominant from recessive inheritance. In small families, in which only one descendant is afflicted and the parent is seemingly normal, one may mistakenly conclude that the inheritance is recessive. Other characteristics of mutational diseases are penetrance, a measure of the proportion of individuals with a given genotype who will show the phenotype, and expressivity, referring to the severity of disease in an affected individual. Variable degrees of penetrance and expressivity are characteristic features of dominant patterns of inheritance but not of recessive ones. There is also a general tendency for dominantly inherited disease to first appear long after birth.