There are a number of different types of genetic errors. Sometimes entire chromosomes may be missing or duplicated. There may be deletions of parts of the chromosome or parts that are misplaced or turned around. There can be errors in the letters of the code, thus causing the wrong amino acid to be used. These errors are called single-nucleotide polymorphisms (SNPs). SNPs are the most common form of variation among people. The error is the use of the wrong letter such that an A (adenine) is switched to a T (thymine). Most of these will not alter the functioning of the person, but some can cause severe disease such a sickle cell anemia. There are many types of sickle cell disease depending upon the gene mutation, but one form is caused when the sequence GAG is changed to GTG — one single letter can cause the destructive disease.
The two most common chromosomal problems causing sterility in females are 47 XXX and 45 XO (Turner’s syndrome). The 47 XXX syndrome occurs in 1 in 1,000 female births and causes premature ovarian deficiency. Turner’s syndrome occurs in 1 in 2,000 female births. Turner’s syndrome is a disease caused by an entire chromosome being absent. Turner’s syndrome results when a person has only one sex chromosome — an X chromosome. This person develops as a female with characteristics such as short stature, a web neck, and a low hairline, and about one-third will have heart defects. These people do not make eggs, so they are menopausal from birth and thus are sterile. However, some people with this problem have a mixture of cells with some having only one but some having two X chromosomes. This condition is called mosaicism. Depending upon how many cells are normal, this person may display the signs of a person with Turner’s but actually have some eggs. She may be able to have child, which is rare. Or she may have early normal egg development but run out of eggs very early in life and thus lose the ability to have her own child. If this condition is established early, it is possible to harvest some of the eggs and freeze them for later use.
A second example of a chromosomal cause of sterility occurs in males. Being a male is determined by the Y-chromosome. A gene on the Y-chromosome directs a man to make sperm. The gene is called the sex-determining region (SRY) and is located on the long arm of the Y chromosome. It is passed unmodified from father to son, and thus any abnormality of the gene will be transmitted to a son.
One region of the SRY gene is called the azospermic factor (AZF), and this has three sections termed the a, b, and c regions. Some men with very low sperm counts or with no sperm in the ejaculate have deletions in this region. If a man had a deletion in the “a” region, he will not have sperm and has what is termed Sertoli-only syndrome. That man will not be able to have children that are genetically his. Thus, this type of mutation cannot be inherited. However, if the man has deletions in the “b” or “c” regions, his count may be low or zero but there may be regions of the testes that do make sperm. This man can undergo a testicular biopsy where a very small amount of testicular tissue is removed and tested to see whether sperm are present. If they are, then these can be used in IVF and the man has the possibility for having genetically his own children. If he has a male child, the child will inherit the same deletion as the father, and thus this type of infertility can be inherited.
Males can also have impaired fertility or even be sterile if they have too many Y chromosomes. The person is then XYY and has what is called Klinefelter’s syndrome. Some men with this problem do have sperm in the ejaculate and others have sperm which must be extracted from the testes. Unfortunately, some will have no sperm and are thus sterile.
Inheriting Diseases that May Impact Fertility — Different Story!
There are genetic causes of infertility that can be passed down from generation to generation, but these usually involve much less of the genetic code. Some are single gene mutations, and some are structural problems with a part of a chromosome being rearranged but not entire chromosome changes.
For males, myotonic dystrophy is an inherited disease that is called an autosomal dominant. This means that if the person has the mutation in just one of the chromosomes, he will have the disease. Thus 50 percent of his offspring will also have the disease. The problem is caused by areas of the gene, which produces a protein required for normal functioning, have unwanted repeated sequences of the letters. The general term for this type of problem is nucleotide repeat diseases, and women can have a similar problem causing the fragile X syndrome. Some of these men have sperm and thus can have children, but some will have no sperm and be sterile. Males can inherit genetic diseases affecting fertility that are single gene defect problems. For these, a mutation of many mutations within a gene causes the gene to malfunction. An example of this is cystic fibrosis. A man with cystic fibrosis will have no sperm in the ejaculate because the tubes that transport the sperm from the testicle to the penis (the vas deferens) do not develop. This is called congenital bilateral absences of the vas deferens and can be treated using sperm extraction from the testis and IVF/ICIS.
One problem for females that has some genetic basis is polycystic ovary syndrome. No single gene has been identified that causes PCOS. Rather, there are a number of genetic mutations that can cause PCOS. Also, patients with PCOS have DNA that has been modified so that the directions for constructing the human are not read correctly — these modifications are called epigenetic factors. Epigenetic modification of DNA helps explain how the environment can alter the way the genetic code is read, and it plays a major role in a number of diseases.
Another type of problem can occur when there are too many copies of a three-letter word, for example egg (a genetic sequence). Fragile X syndrome is an example of this type of genetic error. Fragile X syndrome results when a region of a gene called the FMR1 gene has too many repeated sequences of the genetic word cgg. The FMR1 gene produces a protein that regulates other proteins to make normal nerve connections. The mutation can result in individuals with severe mental compromise. A family with members with severe mental compromise may benefit from genetic testing to determine whether the family has the abnormal FMR1 gene. A normal number of repeats is 5 to 50. If the sequence has more than 200 repeats, then the result is developmental abnormalities in varying degrees. However, where there are 50–200 repeated sequences, the person may have some developmental problems, or a female may have early ovarian failure. So experts often test a woman with premature ovarian failure to determine whether she has too many repeat sequences.
There are a number of single gene defects that affect the fertility of a person. These are being diagnosed more and more so the list is becoming quite long. It is beyond the scope of this chapter to fully explore these diseases.
Shaking the Family Tree for Information
The fact that genetics is playing a larger role in the cause and potential treatment of all diseases makes knowledge about families important. Doctors are now taking a more extensive family history, and if it seems warranted, they construct a genetic diagram (family tree; see Figure 3-2 for an example).
FIGURE 3-2: Diagram of genetic history.
Many people have at least one disease-causing genetic mutation if it occurs on both chromosomes. Fortunately, people have two chromosomes, so the mutation does not cause a clinical problem. But if two people have children and they both have the same mutation, then one out of four children may have the disease. A family tree may show relatives that had symptoms of the diseases which would put the couple on alert to test for the mutation.
Finding Out What’s in Your Genes
You may be asking why your fertility doctor would want to know all of the specifics of your genes and your partner’s