Dr. István Balogh, Dr. János Kappelmayer, Dr. József Tőzsér (2011)
University of Debrecen
Almost all human diseases have genetic components. In the case of multifactorial disorders (see later), many environmental factors are added to the genetic background, while in the case of monogenic disorders, the genetic component can be exclusively responsible for the development of the disease symptoms. A few thousand monogenic diseases are known, and several more are becoming known continuously. With a few exceptions, such as mitochondrial diseases (showing maternal inheritance) and dynamic mutations (see above), monogenic disorders show classical Mendelian inheritance. Mendelian characters are located either on the autosomes or on the sex chromosomes. Depending on the mechanism underlying the genetic disease, the possible inheritance pattern can be autosomal recessive (AR), autosomal dominant (AD), X-linked recessive (XR), X-linked dominant (XD) or Y-linked. Approximately 65% of the monogenic disorders with severe phenotype show autosomal recessive inheritance, while the proportion of the inheritance patterns of autosomal dominant and the X-linked are 20% and 15% respectively.
In the case of genetic diseases which are inherited in autosomal recessive ways, it takes two wrong gene copies for the disease phenotype to develop. Those two mutations are inherited from the parents and they are not necessarily the same. If the child inherits the same mutation from both parents, the genotype will be a homozygous mutant. If the inherited mutations are different, the genotype will be compound heterozygous. The probability of children of heterozygous parents being heterozygous carriers is 50 %, the chance of being wild type and homozygous (or compound heterozygous) genotype is 25 and25% respectively. Therefore, in the case of a child who is not sick, the chance of being a carrier is 67%. Figure 6.1. shows the example of sickle cell anemia but similar picture can be dawn for several thousand monogenic diseases. In conclusion, in the case of autosomal recessive diseases, the affected child is born from unaffected, carrier parents. These disorders affect both sexes. It is important to note that inbreeding (e.g., in isolated populations) significantly increases the risk of the development of such a group of disorders.
In the case of diseases inherited in autosomal dominant way, only one wrong gene copy is enough to develop symptoms. Figure 6.2. shows the example of multiplex endocrine neoplasia type 2 (MEN-2). Both members of generation III has a 50% chance to inherit the disease. In those cases, the analysis of the genetic background, detection of the responsible mutation by some genetic method might help to establish the molecular genetic diagnosis before the onset of the symptoms, it will be possible, therefore, to implement some preventive measures in order to avoid the disease. In the case of autosomal dominant disease, both the child and one of the parents are affected (if the mutation is not de novo). As the inheritance is autosomal, both sexes can be affected.
Disorders with the X chromosome might show either dominant or recessive inheritance. Figure 6.3. shows the inheritance of Duchenne muscular dystrophy (DMD). As the disease shows an X chromosome-linked recessive inheritance pattern, boys are affected in almost every case. There is no cure for DMD, so the molecular genetic diagnosis and carrier diagnosis are of great importance. Two generations can be traced back in the figure. The III/2 boy who is affected by the disease has a sister (III/1). In her case, due to the developments in the recent years in the molecular methods, it is possible to prove or exclude carriership. In the case of a heterozygous carrier female, it is possible to determine the genotype of the fetus in the case of pregnancy. The figure highlights an important phenomenon of the X-linked recessive diseases, namely, the family history of a previously affected male child in the mother's family.
Figure 6.3. Figure 6.3. The family tree of a genetic disease inherited in X chromosome recessive way
The situation is different in disorders showing X-linked dominant inheritance as they can affect both sexes. Female patients are involved in higher numbers, though with usually a milder phenotype. A female patient inherits the affected chromosome with a 50% probability, while all female children of an affected male will have the disease, none of his sons will (as they inherit his Y chromosome in those cases).
No known human disease is located on the Y chromosome. Apart from being responsible for the development of male sex, as it is absent in females, it cannot code any severe diasease-causing gene. Y-chromosome microdeletions are frequently the underyling cause of male infertility. In addition to the sex-determining regions, there are so-called pseudoautosomal regions in both sex chromosomes as well.
Understanding the above-mentioned Mendelian inheritance types seems relatively easy. However, in practice, many factors might make the picture more complicated. If the case of a penetrance is not 100%, it might happen that the carrier does not show the phenotype associated with the disease. Mutations arising de novo result in a phenotype that has not been present in the family before. The situation can be further complicated by intrauterine fetal loss in very severe diseases, inbreeding or imprinting as well.
There are fundamental differences between the inheritance of nuclear and mitochondrial diseases. A special phenomenon of the latter is the maternal inheritance, as the sperm cells do not contribute mitochondria to the zygote. Another important difference is that in the case of mitochondrial diseases the heteroplasmy might be present, as the egg cell has more mitochondria. This means that the even with the same mutation, the phenotypic expression of a mitochondrial disease can vary considerably.
A pathogenic mutation that affects an amino acid position can be formed because of the instability of the genetic material in the genomic region, but there are many examples of mutations that occurred a single time in the course of human evolution. This latter case is called founder mutation. The mutation might disappear in the following generations if evolutionally disadvantageous, or its frequency can be maintained or even increased if advantageous. The mutation site and genetic markers in the regions in close proximity might help us to determine the age of the founder mutation. The smaller the unit with linkage, the more recombinations occurred in the chromosome, so the older the mutation is (Figure 6.4.). A severe, rather common, but usually underdiagnosed iron overload disease, haemochromatosis, provides a good example of the founder effect. One of the most common causative mutations, HFE C282Y, came into being approximately 1500 years ago. Its prevalence nowadays is 4.5%. In this case, the selectionarily advantageous effect of the mutation could be more efficient iron absorption/storage in those periods of human history, when insufficient rather than balanced diet was the norm. This of course means that in our age, when such insufficient, iron-deficient diet no longer persists in Europe, the previously beneficiary mutation becomes harmful by establishing iron overload in the different tissues and organs, mainly in the liver causing irreversible damage through decades.