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{In no situation do we ever recommend that fertility diagnosis or treatment be undertaken without the oversight of a qualified medical practitioner. Please use the enclosed information as quick reference and for discussion aids with your practitioner.}

Why is it important to understand the parts that genes play in infertility? There are at least four reasons.

• 1. Knowledge is power. Understanding the role that genes play in a given couple’s infertility problems allows the couple to make informed decisions about whether they wish to proceed with assisted reproductive techniques or not. A greater understanding of these issues makes the couple more of a partner with their physician.
  
  
• 2. Peace of mind. Many couples learn that they have no known genetic risk factors for infertility or for having a child with a genetic disorder. This allows for less anxiety in an already stressful situation.
  
  
• 3. Genetic testing options. If a couple learn that their offspring is at high risk for inheriting a genetic disorder, they may elect to have pre-implantation genetic testing or the more conventional prenatal testing. Pre-implantation genetic testing (PGD) involves genetic testing of the embryo before it has been implanted in the woman’s uterus to allow for only the embryos without a given genetic disorder to be implanted. Prenatal testing refers to chorionic villus sampling, or CVS, and amniocentesis, more established means of genetic testing before birth. These tests are done at about 11 weeks’ gestation for CVS and from 13 to 18 weeks for amniocentesis.
  
  
• 4. Other medical issues for the couple. Some of the genetic conditions causing infertility can affect the health of the affected person. These include Turner syndrome, polycystic ovaryies syndrome, myotonic dystrophy and others. Knowing these conditions exist can lead to better health care for the affected individual.

Genetic Risks for Women with Infertility

Some women with infertility have a chromosome disorder. Chromosomes are tiny structures located within the nuclei of cells. They contain almost all of our DNA, or hereditary material. If a woman has a chromosome abnormality, she is at risk for not conceiving or for having miscarriages.

Examples:

• Turner syndrome. This is a condition characterized by infertility and short stature, and in some, webbed neck, heart problems, diabetes, and other features. It is due to the absence of one of the X chromosomes or to an abnormality of one of the X chromosomes in most cases. The normal number of X, or sex, chromosomes in females is two.
  
  
• Having three X chromosomes instead of two. This may cause infertility and is associated with an increased risk of having children with other types of chromosome disorders. Women with this chromosome finding usually appear entirely normal.
  
  
• Translocations of chromosomes. In about 2-4% of couples with two or more early miscarriages, one of the members of the couple has a rearrangement of their chromosomes, or translocation, that causes the miscarriages. People with balanced translocations appear normal and are not affected by the translocation except when they attempt to have children.
  
  
• Early menopause. Women with early menopause are at increased risk for having a sex chromosome abnormality, as described above, or for being a gene carrier for a condition known as fragile X syndrome. Fragile X syndrome occurs in about one in 4,000 male births and is less common in females. A genetic test is available to determine whether a woman has an increased risk of having an affected child.
  
  
• Polycystic ovary syndrome. Some women with this diagnosis may actually have a genetic condition called non-classical adrenal hyperplasia. These women have an increased risk for having children with genital abnormalities or life-threatening metabolic crises if the father of their baby is a gene carrier for adrenal hyperplasia. This is a common and under-recognized genetic disorder that can be life-threatening.
  
  
• Myotonic dystrophy. This is an uncommon condition, present in about one in 10,000 people, but it is important to recognize because a woman who is mildly affected has a high risk of having a child who is severely affected. Myotonic dystrophy is associated with muscle weakness, facial features that lack the normal amount of expression, cataracts, balding in the frontal areas of the scalp-and in newborns who are affected, mental retardation. Due to mild symptoms, many people with myotonic dystrophy are unaware until they are older that they have it.

Genetic Risks for Men with Infertility

"Male factor" infertility is more likely to have a genetic basis than female factors. Some of these are listed below.

• 30-36% of men who produce a very low number of sperm or who produce no sperm have a chromosome disorder, including Klinefelter syndrome or a small deletion of part of the Y chromosome. Klinefelter syndrome is a condition in men in which they have an extra X chromosome in some or all of their cells. The extra X chromosome causes the lack of sperm production.
  
  Other features include relatively small testes. Many men with Klinefelter syndrome are not aware of the diagnosis until they undergo an infertility evaluation.
  
  
• Microdeletions of the Y chromosome can cause a low sperm count, zero sperm count or abnormal sperm shape and movement. Men with this finding who undergo intracytoplasmic sperm injection have a high risk of having sons with infertility.
  
  
• In 2-4% of couples with two or more early miscarriages, as noted above, one of the members of the couple has rearranged chromosomes known as a balanced translocation.
  
  
• 1-2% of men with infertility have congenital bilateral absence of the vas deferens, or CBAVD. About 75% of these men have a gene mutation for cystic fibrosis (CF) on one of their #7 chromosomes and a gene variant on the other #7 chromosome known as the 5T allele. Given that one in 27-30 Caucasians in the United States is a carrier for CF, men with this condition who undergo intracytoplasmic sperm injection (ICSI) have an increased risk of having a child affected with CF.
  
  
• Other medical conditions that are associated with male infertility include myotonic dystrophy, which is discussed above; polycystic kidney disease; and several others.

How Can I Find Out if I Have Any of These Genetic Problems?

Couples with infertility should see a genetics professional before proceeding with advanced reproductive techniques, such as ICSI. A detailed personal and family history will be obtained, and in some cases, genetic testing will be recommended. Because of the advances in genetics knowledge, it is difficult for infertility doctors or obstetricians to keep up with the field of genetics.

What Are Some Reasons for Genetic Testing?

• Couples with two or more early miscarriages: chromosome analysis for both.
• Men with azoospermia or severe oligospermia and small testes: chromosome analysis
• Men with azoospermia or severe oligospermia and normal findings on physical exam: microdeletion of Y chromosome testing
• Men with CBAVD or congenital unilateral (on one side) absence of the vas deferens: cystic fibrosis testing at a laboratory that performs tests for many mutations in the CF gene; also specify 5T allele testing, as it is not routinely performed in most labs
• Women with premature menopause: chromosome analysis and fragile X DNA permutation analysis
• Women with polycystic ovary syndrome: consider referral to hormone specialist, or endocrinologist, for adrenal hyperplasia testing
• Couples of certain ethnic and racial groups who are at increased risk of being gene carriers of such conditions as cystic fibrosis, Tay-Sachs disease, sickle cell anemia and many others.

How Do I Find a Genetics Specialist?

Ask your doctor or look on the web site, www.GeneTests.com. It has a listing of genetics clinics throughout the country.

About the author: Linda Marie Randolph, M.D., is a clinical geneticist specializing in the field of infertility. She is the Visiting Assistant Clinical Professor of Pediatrics, Keck School of Medicine, University of Southern California—Division of Medical Genetics, based at Childrens Hospital Los Angeles.