Modes of Inheritance

Since most genes are normal, we often become aware of specific genes only when they change in some unusual manner.  These changes are called mutations.  By changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause disease, or what is sometimes called a genetic disorder.  Such disorders are usually inherited (passed on from one generation to another) in a simple ‘Mendelian’ pattern as autosomal dominant, autosomal recessive or X-linked conditions. ‘Autosomal’ indicates that the gene lies on the non-sex chromosomes (chromosomes other than the X and Y chromosomes), and so both males and females are usually affected in equal numbers in successive generations.

Autosomal dominant inheritance

When a mutation of only one member of a paired gene (remember we all carry two copies of each gene, of which one comes from the mother and one from the father) is sufficient to cause disease, the inheritance pattern is described as ‘autosomal dominant’.  An affected individual will possess one copy of a mutation and so can pass on either their normal or mutant (disease-bearing) chromosome. Therefore as each child has the same chance (50%) of inheriting the mutated gene, an affected individual would be predicted to have 50% affected and 50% unaffected offspring (see figure 1A). Usually, autosomal dominant conditions do not occur in the offspring of unaffected individuals. However rarely, an individual can carry an autosomal dominant mutation but does not develop the disease, perhaps because of the effects from other genes, and such a mutation is said to be ‘incompletely penetrant’.  Examples of conditions in plain people inherited in an autosomal dominant fashion include a bleeding disorder know as factor V heterozygosity, and several types of dystonia.  In each case, the disorder tends to appear over time in a ‘vertical pattern’, as the mutation is passed from one generation to the next.  

Autosomal recessive inheritance

Other conditions, however, are manifest only when the mutation is present on both chromosomes of the pair.  The majority of disorders studied by Windows of Hope are inherited in this pattern which is described as ‘autosomal recessive’. Genes causing this kind of condition generally do not cause problems in carriers, that is, individuals with only one copy of the mutant gene (referred to as ‘heterozygotes’). Thus the parents (carriers) display no features of the disease as the ‘normal’ copy prevents the disease from occurring, and carrier status does not affect the mother or father physically, mentally or in any other way (usually the only consequence of being a carrier of a recessive genetic trait is the possibility of transmitting the particular genetic trait to a child). Therefore most families are not aware that they carry genes for a disease until the birth of an affected child. As each parent possess a normal and a ‘mutant’ chromosome, there are three possible outcomes among the children. As can be seen in Figure 1B, by chance one in four (25%) of the offspring would be expected to develop the genetic disease. Cystic fibrosis is an example of an autosomal recessive condition.

X-linked inheritance

Some conditions such as hemophilia B follow an X-linked pattern of inheritance. The term ‘X-linked’ refers to the location of the disease gene on the X chromosome. Females posses two ‘X’ chromosomes, whereas males posses one ‘X’ and one ‘Y’ chromosome. Therefore X-linked conditions usually affect males more often and more severely than females, because females with a mutation in a gene on the X-chromosome usually have a non-mutated gene on their other X-chromosome which can compensate for the mutation. Females with a recessive mutation in a gene on one X chromosome and a normal copy of the gene on the other X chromosome are carriers (if the condition is dominant, they may also be affected).

Figure 1

(A) Autosomal dominant inheritance in which half of the offspring would be likely to inherit the mutant gene ('r') from the affected parent (shown in red) and be affected. (B) Autosomal recessive inheritance in which one in four (25%) of the offspring would be likely to inherit both copies of the mutant gene and be affected (shown in red); another 25% of the offspring would not be likely to inherit either mutant gene and so not carry the condition (shown in blue).  However, half of the children will be carriers of the mutation just like their parents (purple).