A number of human genetic diseases occur because of mutations in imprinted genes or in the control sequences responsible for setting, resetting or controlling imprinted regions. For example, if a person carries a mutation in an imprinted gene, the disease will be expressed only if the mutation is inherited from the parent whose gene is expressed. Imagine a mutation in a gene that is imprinted in the maternal genome. If a mutation in this gene is inherited from one’s mother, the disease will not occur because it is the father’s gene that is expressed. However, if the mutation is inherited from one’s father, the disease will be evident.
Mutations are classified on the basis of the extent of the alteration. Large mutations, which include alterations to chromosome structure and number, are relatively rare because most cause such major disruptions to development that the fetus is naturally aborted. However, certain alterations are not so immediately lethal, and the fetus can survive with a characteristic disorder. Down syndrome is one such case. It involves an error in the division of chromosome 21 that results in trisomy (three copies of a chromosome instead of two are inherited), bringing the total number of chromosomes to 47 instead of 46. Many characteristics such as distinctive facial features and mental retardation result from the presence of this extra chromosome. Smaller mutations are more common and include point mutations, in which substitution of a single nucleotide base occurs, and deletion or insertion mutations, which involve several bases. Point, deletion, and insertion mutations may cause an abnormal protein to be synthesized or may prevent the protein from being made at all.
Mutations that occur in the DNA of somatic (body) cells cannot be inherited, but they can cause congenital malformations and cancers; however, mutations that occur in germ cells—i.e., the gametes, ova and sperm—are transmitted to offspring and are responsible for inherited diseases. Each gamete contributes one set of chromosomes and therefore one copy (allele) of each gene to the resultant offspring. If a gene bearing a mutation is passed on, it may cause a genetic disorder.
Genetic diseases caused by a mutation in one gene are inherited in either dominant or recessive fashion. In dominantly inherited conditions, only one mutant allele, which codes for a defective protein or does not produce a protein at all, is necessary for the disorder to occur. In recessively inherited disorders, two copies of a mutant gene are necessary for the disorder to manifest; if only one copy is inherited, the offspring is not affected, but the trait may continue to be passed on to future offspring. In addition to dominant or recessive transmission, genetic disorders may be inherited in an autosomal or X-linked manner. Autosomal genes are those not located on the sex chromosomes, X and Y; X-linked genes are those located on the X chromosomes that have no complementary genes on the Y chromosome.
Females have two copies of the X chromosome, but males have an X and a Y chromosome. Because males have only one copy of the X chromosome, any mutation occurring in a gene on this chromosome will be expressed in male offspring regardless of whether its behaviour is recessive or dominant in females. Autosomal dominant disorders include Huntington's chorea, a degenerative disease of the nervous system that usually does not develop until the carrier is between 30 and 40 years of age. The delayed onset of Huntington's chorea allows this lethal gene to be passed on to offspring. Autosomal recessive diseases are more common and include cystic fibrosis, Tay-Sachs disease, and sickle cell anemia. X-linked dominant disorders are rare, but X-linked recessive diseases are relatively common and include Duchenne's muscular dystrophy and hemophilia A.
Most genetic disorders can be detected at birth because the child is born with characteristic defects. Thus these abnormalities are congenital (existing at birth) genetic disorders. A few genetic defects, such as Huntington's chorea mentioned above, do not become manifest until later in life. Hence it may be said that most but not all genetic diseases are congenital.
Conversely, some congenital diseases are not genetic in origin; instead they may arise from some direct injury to the developing fetus. If a woman contracts the viral disease German measles (rubella) during pregnancy, the virus may infect the fetus and alter its normal development, leading to some malformations, principally of the heart. These malformations constitute a congenital disease that is not genetic.
Further confusion often arises over the terms genetic and familial. A familial disease is hereditary, passed on from one generation to the next. It resides in a genetic mutation that is transmitted by mother or father (or both) through the gametes to their offspring. Not all genetic disorders are familial, however, because the mutation may arise for the first time during the formation of the gametes or during the early development of the fetus. Such an infant will have some genetic abnormality, though the parents themselves do not. Down syndrome is an example of a genetic disease that is not familial.