Obstetrics & Gynecology in Minnesota

Genetics

Genetic testing is present in all areas of medicine today. It is no surprise that genetic testing is becoming more frequent in the infertility clinic. Genetics is the study of genes. Genes are encoded in DNA which is a chemical clumped together in distinct units called chromosomes. Genetic tests can identify both the number and structure of these chromosomes, as well as problems in specific genes. Normally, men and women have 46 chromosomes that exist as 23 matched pairs. One of these pairs determines the sex of the person with women possessing two X chromosomes. In contrast, men have one X chromosome and one Y chromosome.

Aneuploidy (chromosome studies, karyotype)

Aneuploidy is the defined as an abnormal number of chromosomes. This is detected by a test called a karyotype. The karyotype can identify chromosome number, rearrangements and sometimes deletions (loss of a portion of the chromosome) if they are large.

Chromosome studies are done for a wide variety of indications including advanced age, frequent miscarriages, male factor infertility, amenorrhea and premature ovarian failure. In addition, chromosome studies are frequently advised for relatives of persons with chromosome abnormalities. Chromosome studies are often necessary to provide the most appropriate reproductive and genetic counseling for a particular couple.

About four percent of men requiring ICSI treatment for male infertility have chromosomal abnormalities (such as abnormal chromosome structure — e.g., translocations or abnormal chromosome numbers — chromosomal aneuploidy). In some cases these types of defects may result in an increased likelihood of pregnancy loss, birth defects or the birth of a child with a chromosomal abnormality. Patients may wish to discuss testing for chromosomal abnormalities with their physician before they undergo treatment with IVF and ICSI.

A decline in egg quality occurs as maternal age increases leading to an increased incidence of chromosomal abnormalities in embryos, fetuses and babies alike. Similarly, some structural chromosomal abnormalities in the mother can result in frequent miscarriage or a baby with chromosomal aneuploidy.

Screening for chromosomal aneuploidy at the embryo stage is now an option for couples at some IVF centers using preimplantation genetic diagnosis.

Cystic fibrosis

Cystic fibrosis (CF) is the most common autosomal recessive disease in the western world. CF also commonly causes male factor subfertility. The classical CF symptoms are progressive lung disease, elevated sweat electrolyte levels and congenital bilateral absence of the vas deferens (CBAVD) resulting in azoospermia (no sperm in the semen). However, the symptoms are variable and may be mild.

Over 700 mutations have been identified in the cystic fibrosis (CFTR) gene. The most frequent mutation accounts for about 70-75 percent of mutations in the North American population. Specific mutations of the CFTR gene are associated with CBAVD in the absence of other symptoms. Up to 80 percent of men with CBAVD with no clinical symptoms of CF have detectable mutations in the CFTR gene. Recent studies have also noted an increase presence of CFTR gene abnormalities in men with otherwise unexplained low sperm counts.

If CAVD is diagnosed it is important for the male to undergo testing for CFTR mutations before proceeding with IVF. If a cystic fibrosis gene defect is found in the male partner, but not the female partner, then their son(s) will be at an increased risk for having the same CAVD infertility disorder as the male partner. If cystic fibrosis gene defects is found in both partners, then genetic counseling is required because of the high risk of having a child affected with cystic fibrosis. In this scenario, options for treatment could include gamete donation or preimplantation genetic diagnosis.

At present, the American College of Medical Genetics recommends that CF testing should be offered to the following groups who may be planning a pregnancy: those with family history of cystic fibrosis, non-Jewish Caucasians and Ashkenazi Jews.

Sex-linked disorders

Genes for sex-linked disorders are present on the X or Y chromosomes. Abnormalities in genes on the Y chromosome will only affect males. However, abnormalities in genes on the X chromosome can affect both males and females but generally affect males more severely than females. Examples of X-linked disorders include hemophilia and Duchenne muscular dystrophy.

Y chromosome abnormalities (microdeletions)

The Y chromosome contains important genetic information required for the formation and function of the testes. Many men who have decreased sperm counts also have deletions of part of the Y chromosome even when a chromosome study has come back normal.

There appears to be a rough correlation between the frequency and size of these deletions and the severity of the infertility problem. Around 10 to 20 percent of men with no sperm in the ejaculate (azoospermia) carry deletions of Y chromosomal DNA. A smaller percentage (perhaps five percent) of men with extremely low sperm counts also carry deletions.

Current evidence suggests that Y chromosome deletions can be passed on to male offspring via ICSI (intracytoplasmic sperm injection). This means that sons of fathers with Y chromosomal deletions will probably inherit some form of male factor infertility.