Genetics of Male Infertility

Genetics of male infertility

Genetics is an exciting and rapidly developing field that is transforming our understanding of the body and how to treat disease. The genes contained in our chromosomes encode the building instructions for every cell in our body, so it is not surprising that genetic problems can interfere with male fertility. Genetic abnormalities are found at a much higher rate in men having fertility problems, with various studies finding an eight- to hundredfold increased risk of genetic problems in this population of men. Genetic abnormalities can impact fertility in three ways: an inability to conceive a pregnancy, an elevated risk of early pregnancy loss, and a risk of transmitting genetic abnormalities to biologically related children.


A Review of Basic Genetics

Humans normally have forty-six chromosomes (twenty-three pairs of chromosomes). Forty-four of the chromosomes are what are called autosomes, and two are the sex chromosomes, which can be either an X chromosome or a Y chromosome. Women have two X chromosomes (XX), and men have one X and one Y (XY). A person’s karyotype is the number and structure of his or her chromosomes. A person’s phenotype is his or her observable physical characteristics, which result when the person’s genes interact with the environment.

When sperm and eggs are produced by males and females, respectively, the chromosomes split so that each sperm or each egg receives twenty-three chromosomes. When fertilization occurs, the egg and sperm from each partner combine, and each contribute its twenty-three chromosomes to provide the resulting embryo with the full set of forty-six chromosomes. The Y chromosome, if present, makes that embryo become male.


There are two important, distinct areas on the Y chromosome that we know impact male fertility:

1) SRY (sex-determining region Y) gene. Normally present on the Y chromosome, this gene makes the fetus become a phenotypic male—that is, the child looks anatomically like a male. If the SRY gene is not present, the child will look anatomically like a female.

2) AZF (azoospermic factor) region of genes. This region is important for normal sperm production. If it is missing (called a Y chromosome microdeletion), these men usually have little or no sperm production.


Causes of Genetic Problems

Genetic problems can occur in one of two ways: through spontaneous gene mutations or by inheriting an abnormal gene from one of the parents. Many genetic problems are clearly inherited from the parents, such as the cystic fibrosis gene. However, not all genetic problems affecting sperm production are passed from generation to generation. Men with extremely low sperm counts are sometimes confused as to how they can have a genetic sperm production problem when their father (and often their siblings as well) have had no problems conceiving children. The reason is that many of these genetic male-factor problems result from spontaneous new mutations. If their fathers had had the same genetic problem, then the patient likely would not have been conceived, since many of the current high-tech fertility options were largely not available to the previous generation (the first successful IVF cycle was in 1978).


New mutations can arise within a man’s chromosomes via several mechanisms:

1) Deletions. Genes can be deleted from chromosomes for many different reasons, including abnormalities that occur during cell division.

2) Translocations. Genetic translocations occur when genetic material is exchanged abnormally between a person’s chromosomes. No genetic material is lost during this rearrangement, so the person with the translocation typically does not have any other apparent health problems. However, when the chromosomes are split up during egg or sperm formation, sometimes the egg or sperm can end up with too much or too little genetic information. Depending on the translocation type, this can result in an increased risk of miscarriage, chromosomal abnormalities (such as Down syndrome), and certain types of cancer or other health problems.

3) Inversions. Similar to translocations, inversions do not involve the loss of genetic material in the parent. Rather, there is a rearrangement of the order of the genes within a chromosome. Again, this typically does not impact the parent as much as it can affect offspring, since during sperm formation the amount of DNA that each sperm receives might be unbalanced.


Genetic Counseling

Genetic counselors are clinical specialists who are trained in evaluating genetic abnormalities and discussing their potential consequences with patients. They are often found working in children’s hospitals, since this is the population in which the majority of genetic problems are diagnosed, but they regularly work with adults too.

Patients who have a karyotype abnormality should have genetic counseling. This can help to determine the odds that their genetic problems will impact their own fertility or the health of their offspring. In addition, genetic counselors can provide valuable information about general health concerns associated with certain genetic problems, such as Klinefelter’s disease. Men with Y chromosome microdeletions do not necessarily need formal genetic counseling if they are working with a male fertility specialist, since these problems do not generally impact other areas of their health besides reproduction. However, these patients need to know that if their own sperm are used, then any resulting male offspring will harbor these same microdeletions.

Genetic Testing


Currently, there are four main genetic tests that can be performed in men with fertility problems:

1) Karyotype testing. Evaluates the chromosomes for problems resulting from deletions, translocations, and inversions. Potential abnormalities that can be detected with karyotype testing include:

         1) Klinefelter’s disease

         2) 46 XX syndrome

         3) 47 XYY syndrome

         4) Translocations and inversions, both of which can lead to an increased risk of recurrent pregnancy loss

2) Y chromosome microdeletion (YCMD) testing. Looks for specific deletions in the AZF region of the Y chromosome that are known to encode for sperm production

3) Cystic fibrosis testing. Men who carry two copies of the cystic fibrosis gene can have sperm blockage problems (congenital bilateral absence of the vas deferens, CBAVD), as well as the disease cystic fibrosis.

4) Sperm DNA testing. Evaluates the integrity of the sperm DNA itself.


The field of genetics is rapidly evolving, and new genes are being discovered every year. Although the genes of the AZF region are extremely important, there are certainly many more genes involved in maintaining normal sperm production, and most of these have not yet been identified and so cannot yet be tested for. Therefore, if genetic testing results on a man come back as normal, this does not completely rule out the presence of genetic problem; it merely means that the man does not have any genetic abnormalities that we can test for at this time.  The other factor to keep in mind is that there are currently no gene therapies or embryonic stem cell treatments that can correct fertility-related genetic abnormalities.


Deciding on whether to perform genetics testing

The value of a genetic test must therefore be weighed against the financial costs of that test. Factors to consider when deciding whether to proceed with genetic testing include:


1) Cost of Genetics Testing

Genetics testing is sometimes covered by insurance depending on your individual state mandates.  I generally use ICD-10 code E29.9 (testicular failure) as the diagnosis code for karyotype and Y chromosome microdeletion testing, but code N46.9 (male infertility) can also be used if you have coverage for infertility testing. Please see the "Genetics and Advanced Sperm Testing Costs" section of this website for more detailed information.


2) Inheritance of Genetic Problems

How important it is to a particular couple that they may be passing on possible genetic abnormalities to their offspring. Remember, genetic abnormalities that we cannot yet test for can be passed on as well.


3) Impact on Fertility Chances

The presence of certain genetic problems may have a profound impact on the chances of that couple conceiving a child who is biologically related to the male partner.


4) Impact on the Man's Overall Health

Some genetic issues (such as Klinefelter’s) can increase the chances of other general health problems in the male, while other (such as Y chromosome microdeletions) seem to only affect their fertility potential.


Indications for Genetics Testing 


Karyotype and Y Microdeletion Testing

Currently, the established fertility guidelines recommend karyotype and Y chromosome microdeletion genetic testing for men with a sperm count of under 5 million/cc and no other known significant causes of infertility (such as obstruction or previous chemotherapy, among others). However, genetic testing can be expensive, and in some men with relatively low sperm counts, the chance of finding a genetic abnormality with current testing capabilities is very low. A cost-benefit analysis therefore needs to be made for each couple as to whether the genetic information they can obtain from genetic testing has the potential to be useful enough to justify its cost.

In general, men with no sperm in the ejaculate (azoospermia) who have no blockage issues have about a 15–20 percent chance of having genetic testing show an abnormal karyotype or Y chromosome microdeletion. In contrast, men with oligospermia (low sperm count) have only a 5–6 percent chance of having a genetic abnormality found upon testing.

In a recently published paper, the Cleveland Clinic evaluated costs and benefits and concluded that a better cutoff for ordering genetic testing would be a density of 2.5 million sperm/cc or under. This is the criteria that I currently use in my practice, since I almost never find that genetic testing is useful in men with sperm densities of between 2.5 and 5 million/cc. An exception to this general rule is found in men whose partners have had unexplained recurrent pregnancy loss. In this situation, I will often order a karyotype test in the male partner (regardless of his sperm count), since translocations and inversions may contribute to pregnancy loss in men with fairly high sperm counts.


Cystic Fibrosis Screening

The CFTR (cystic fibrosis transmembrane conductance regulator) gene is associated with cystic fibrosis. CFTR testing is indicated in two circumstances: if there is concern about a congenital vasal abnormality, or if the female partner is found to be a cystic fibrosis gene carrier, in order to assess the risk of any subsequent children developing the disease.

Otherwise, if a man has sperm in the ejaculate and no suspected genital duct structural abnormality (such as a non-palpable vas deferens on one side), then CFTR testing is not indicated.


Sperm DNA Testing

The integrity of sperm DNA can be assessed by looking at the ability of sperm DNA to resist fragmentation. Indications for sperm DNA testing include:

      1) Normal semen analysis but unexplained persistent infertility

      2) Recurrent unexplained pregnancy loss

      3) Recurrent unexplained IVF failure

Some clinicians also use sperm DNA testing to assess the integrity of sperm DNA in various at-risk men, such as those who have had prior chemotherapy or those considered to be of advanced paternal age (although no official guidelines have been established for these groups of patients). See the "Advanced Sperm Testing" section for more detailed information about sperm DNA testing.

Klinefelter’s Disease


Klinefelter’s is the most common karyotype abnormality in male fertility. This genetic abnormality is cause by having an extra X chromosome, and therefore these men have forty-seven chromosomes (instead of forty-six), with two X chromosomes and one Y chromosome (instead of one X and one Y). Another way to express it is that men with Klinefelter’s have a 47 XXY karyotype (normal for a male is 46 XY). Klinefelter’s affects one in five hundred live male births and is the cause of 14 percent of cases of non-obstructive azoospermia. One known risk factor for developing Klinefelter’s is increased maternal age.



Classic findings seen in men with Klinefelter’s disease include:

      1) Small, firm testes

      2) Gynecomastia (enlargement of breast tissue)

      3) Azoospermia (a small percentage of men with Klinefelter’s have small amounts of sperm in the ejaculate)


Men with Klinefelter’s often also have delayed or decreased development of secondary sexual characteristics, such as body and facial hair and muscle development. Other common findings include:

      1) Tall stature

      2) Obesity

      3) Eunuchoid body proportions (lower body segment longer than upper body, arm span 5 cm or more longer than height)


However, there is very wide variation between men with Klinefelter’s disease. “Classic” Klinefelter’s patients are often diagnosed at a younger age, as there is usually a lack of development of normal secondary sexual characteristics at puberty. However, many men with Klinefelter’s appear completely normal with the exception of having small, firm testicles. These men can experience fairly normal pubertal changes and are diagnosed only as adults when they attempt to have children.


Fertility Potential with Klinefelters

Men with Klinefelter’s generally have:

      1) Azoospermia

      2) Elevated FSH levels

      3) Elevated LH levels

      4) Low testosterone levels


In some circumstances (10–15 percent of the time), a man with Klinefelter’s can have a condition called mosaicism, in which a certain percentage of his body cells have a 47 XXY karyotype and the rest are normal 46 XY. These men typically have higher testosterone levels and larger testicle sizes. Many of these men are still azoospermic, but approximately 50 percent have very small amounts of sperm in the ejaculate (an average of about 4 to 5 million sperm per cc).


Other Health Concerns

Men with Klinefelter’s are at an increased risk of other general health problems, so they need to have a primary care physician who is familiar with the potential medical problems associated with a 47 XXY karyotype.

Some of the health problems that Klinefelters patients are at an increased risk for include:

      1) Diabetes

      2) Extragonadal germ cell tumors

      3) Leukemia

      4) Breast cancer (mean age of diagnosis is sixty-five years)

     5) Non-Hodgkin’s lymphoma

      6) Osteoporosis (possibly in combination with vitamin D deficiency)

      7) Clotting abnormalities, such as deep venous thrombosis or pulmonary embolism

      8) Adrenal gland insufficiency

      9) Lung cancer

     10) Mitral valve prolapse

     11) History of undescended testicles (in up to 10–25 percent of men)


It’s important to remember that despite the increased risk of certain forms of cancer in these men, the majority of them do not develop those malignancies.  I do recommend genetic counseling for all men with a diagnosis of Klinefelter’s disease.

General health maintenance recommendations include:

      1) Monitoring of labs, including testosterone, estradiol, cortisol, hematocrit, TSH, and vitamin D

      2) DEXA scan to evaluate for osteoporosis

      3) Echocardiogram to look for mitral valve prolapse


Fertility Options with Klinefelters


Almost all men with Klinefelter’s have azoospermia. Options for fatherhood include:

      1) Adoption

      2) Intrauterine insemination with donor sperm

      3) Donor embryos

      4) Attempted sperm extraction combined with IVF/ICSI


Sperm can sometimes be found in the testicles of azoospermic men with Klinefelter’s (or mosaic Klinefelter’s) and used successfully with IVF/ICSI. Microscopic testicular sperm extraction (mTESE) is generally used due to its relatively high success rates in finding sperm (see “Azoospermia" section for more information on mTESE in men with Non-obstructive Azoospermia).

Prior to undergoing mTESE, the man’s testosterone level should be raised to greater than 250 ng/dL using medications such as anastrazole. This will improve the chances of finding sperm. Y chromosome microdeletion testing is also recommended, since approximately 5–10 percent of men with Klinefelter’s also have YCMDs.

Centers using mTESE in men with Klinefelter’s disease have had success rates of 40–70 percent in terms of finding enough sperm for a fresh cycle of IVF/ICSI. Most sperm that are surgically retrieved are genetically normal. Supposedly, the use of extracted sperm has not resulted in the live birth of any children with Klinefelter’s, but a few aborted fetuses have shown genetic abnormalities. Some centers recommend the use of preimplantation genetic diagnosis (PGD) due to the increased risk of aneuploidy (an abnormal number of chromosomes) in the embryos (see below for more information on PGD).

Chromosome Microdeletions


Only men have a Y chromosome, and the genes that encode for normal sperm production are found on this chromosome. Therefore, deletions on the Y chromosome can have a profound impact on semen parameters if they affect the genes that control sperm production. The AZF (azoospermic factor) region has been found to play a very important role in sperm production. It is divided into three sections:


•          AZFa (also called DYS273 and DYS275, or P5/proxP1 by some labs)

•          AZFb (also called DYS209 and DYS224, or P5/distP1 by some labs)

•          AZFc (also called DAZ and SPGY, or b2/b4 by some labs)


Deletions in the AZF region are found in 6–14 percent of men with severe oligospermia and in 3–18 percent of men with complete azoospermia. The impact on sperm production depends on which of the AZF sections is missing:


1) AZFa deletion, which results in a severe production problem causing complete azoospermia, is found in about 1 percent of azoospermic men

2) AZFb deletion, which also results in a severe production problem causing complete azoospermia, is found in about 1–2 percent of azoospermic men

3) AZFc deletion, which results in a slightly less severe production problems, is found in up to 13 percent of azoospermic men and 6–14 percent of men with severe oligospermia


Testing for YCMD

The ICD-10 diagnosis code for YCMD testing is E29.9 (testicular failure), but code N46.9 (male infertility) can also be used if you have infertility testing coverage.  Please see the "Genetics and Advanced Sperm Testing Costs" section of this website for more detailed information on the costs of testing if not covered by insurance.

Fertility Options in men with YCMD's

In men with an AZFa or AZFb deletion, there is no sperm production at all, and attempted testicular sperm extraction will not be successful; adoption, donor sperm, and donor embryos are the only options for having a child. Approximately 40–55 percent of men with only AZFc deletions can have small islands of sperm production that can be found by sperm extraction techniques (such as mTESE) and used in conjunction with IVF/ICSI (see “Azoospermia" section for more information on mTESE in men with Non-obstructive Azoospermia).


Genetic Implications of YCMD's

Y chromosome microdeletions (YCMDs) are not yet known to be associated with significant health problems, other than potentially lower testosterone levels and a possible increased risk of testicular cancer. However, it must be remembered that if sperm are used from a man with YCMDs, then those same YCMDs are going to be passed on to any male children the couple conceives, presumably resulting in similar testicular function problems for those boys. By the time these male children reach reproductive age, there may be new, innovative treatments available (such as gene or stem cell therapy), but this is by no means guaranteed.

Cystic Fibrosis testing


Cystic fibrosis (CF) is a severe respiratory disease that can also affect the function of the liver, pancreas, and intestines. CF patients have thick mucus secretions that lead to recurrent lung infections, and in the past, few people with CF lived to reproductive age. However, with the advent of better antibiotics and respiratory care, CF patients are living much longer, healthier, and more productive lives.

The CFTR (CF transmembrane conductance regulator) gene is responsible for the movement of electrolytes out of the cells. If the CFTR gene is not working, then water does not flow out of the cells into the mucus, resulting in abnormally thick mucosal secretions. Every person has two CFTR genes, and only one of them needs to be working properly to have normal mucus secretions. Therefore, CF is known as a recessive gene, in that both CFTR genes need to have mutations in order for a person to have actual cystic fibrosis disease. People with only one mutated CFTR gene are called carriers and are generally completely asymptomatic, although they will pass this gene on to 50 percent of their biological children.


Clinical Presentation

Many different possible mutations of the CFTR gene exist—over eighteen hundred distinct mutations have already been identified. The most common mutation is the delta F508 deletion, which represents about 70 percent of CFTR gene mutations found on testing. Some mutations are more severe than others in terms of their impairment of the regulation of normal mucosal viscosity. Because of this wide variety of possible mutation combinations, there is a spectrum of cystic fibrosis disease severity. In general, severe impairment of CFTR action results in cystic fibrosis disease and congenital bilateral absence of the vas deferens (CBAVD), whereas mild impairment causes only CBAVD. In between those extremes, there are combinations that can include varying degrees of respiratory impairment combined with CBAVD.

Examples include:

                              Genes                                                      Findings

                   2 normal CFTR genes                             Normal, no problems

                   1 normal CFTR gene                  CFTR carrier, no clinical problems

                   2 severe CFTR mutations            Cystic fibrosis disease and CBAVD

                   2 mild CFTR mutations                                 CBAVD only

         1 mild and 1 severe CFTR mutation   Can have CBAVD with or without some degree of respiratory disease


Note: all men with two mutated CFTR genes generally have CBAVD, but not all men with CBAVD have CFTR mutations (see below).


Congenital Bilateral Absence of the Vas Deferens (CBAVD)

The vas deferens carries the sperm from the epididymis to the ejaculatory ducts during ejaculation. Men with two abnormal CFTR genes have abnormal development of the vas deferens and/or ejaculatory ducts, resulting in sperm blockage problems (obstructive azoospermia).

In its most common form, men with CBAVD are missing the entire vas deferens on each side, as well as the body and tail of the epididymis, at least part of the ejaculatory ducts, and sometimes even the seminal vesicles. This results in the complete absence of all fluid from the testicles and seminal vesicles in the ejaculate (but the prostatic fluid can still enter the ejaculate).

The clinical presentation of this classic CBAVD scenario includes:

      1) No palpable vas deferens in the scrotum on either side

      2) Ejaculate with low volume (under 1.0 cc), acidic pH (under 7.0), and no fructose (since the ejaculate only contains fluid from the

                      prostate gland)

      3) Ejaculate often looks clear and watery


Variants of CBAVD can occur. Some men are missing only parts of the vas deferens (called ”skip lesions”) and therefore may have a palpable vas (or part of the vas) in the scrotum on one or both sides. Some men with CBAVD variants may also have an intact ejaculatory duct and therefore have ejaculate with normal alkalinity and fructose, but without sperm. These variants, however, represent a minority of men with CBAVD.


Congenital Unilateral Absence of the Vas Deferens (CUAVD)

CUAVD typically presents with a non-palpable vas deferens on only one side. If the other testicle and genital duct system are intact, semen analysis may be normal. Missing a vas deferens on one side can be associated with CFTR mutation problems about 40 percent of the time. Another cause of CUAVD that is not related to a CFTR gene mutation is a problem with the development of the mesonephric duct during embryo development. These men are generally missing (on one side) their vas deferens, seminal vesicle, kidney, ureter, and part of their epididymis. CFTR mutation screening and renal ultrasound evaluation are recommended for all men with only one palpable vas deferens.


Congenital Epididymal Obstruction

Some men are born with obstructions in each epididymis. This results in complete azoospermia with a normal semen volume, pH, and fructose. On physical examination, the epididymis on both sides typically feels enlarged or engorged. Congenital epididymal obstruction is associated with a CFTR gene mutation in approximately 45–50 percent of cases, and therefore CFTR screening should be offered to all of these men. Fertility treatment includes microsurgical reconstruction (see "Fertility Following Vasectomy" section for more information on the vasoepididymostomy procedure) or sperm extraction combined with IVF/ICSI (see below).


Fertility Treatment of CBAVD

CBAVD and its variants (other than congenital epididymal obstruction) are generally not amenable to surgical reconstruction. Testicular sperm production is usually normal, but FSH blood testing is still recommended in order to make sure sperm production is still good (see “Hormone Testing and Interpretation” section).  If the FSH is normal, then sperm can be extracted from the testicles and used with IVF/ICSI with anticipation of good success rates (see “Azoospermia" section for more information on sperm extractions in men with Obstructive Azoospermia).

For all men with CFTR mutations, it is important to always screen the female partner for CFTR mutation carrier status. If she is found to also be a carrier of a CFTR gene mutation, then the couple may want to consider preimplantation genetic diagnosis (discussed later in this chapter) to limit the chance of any offspring having cystic fibrosis disease.


Genetic Testing in Men with CBAVD

Men who are suspected of having CBAVD are advised to have genetic testing done to look for mutations of the CFTR gene. CFTR mutation testing is also recommended in men with any other congenital genital duct abnormalities, such as congenital epididymal obstruction or CUAVD (see above). Although there is no gene therapy available at this time, this genetic testing provides important health information for any of the man’s siblings and for any children who are conceived, who might be carriers of the same mutations.

If you are considering testing for CFTR mutations, there are several factors to be aware of. One is that CFTR mutations are more common in some ethnic groups than others:

Another is that eighteen hundred different CFTR mutations have been identified, and different specific CFTR mutations are more common in certain ethnic groups. The CF screening test panels used most often have been designed to check for the CFTR gene mutations most frequently found in the Caucasian population, since this group has the highest incidence of the mutation. Therefore, the chance of a false negative result (in which the gene that a person has cannot be identified by a regular screening panel) is higher in non-Caucasian populations.

Most commercial CF tests are designed to look for the more severe CFTR mutations that lead to cystic fibrosis. They therefore may not look for some of the more common mild CFTR mutations that cause CBAVD (but not CF). An example of this is the 5T allele of intron 8, which is a common mild CFTR mutation that is not routinely checked in regular CF screening panels.

Which CF screening test should be used? Several different commercially available options exist for CF screening, including a twenty-three-mutation screen, a ninety-seven-mutation screen, and full gene sequencing (note: different labs may modify this a little, and so may have a 100 mutation screen instead of a 97 mutation screen, and these would be essentially equivalent). In general, the standard twenty-three-mutation screen is used in couples without fertility issues who are undergoing a basic screening looking for the most common genes causing CF disease. I prefer to use the ninety-seven-mutation screen (which includes the 5T allele), as it looks at more of the genes that cause mild CFTR functional loss and can result in CBAVD without CF disease. Full gene sequencing is quite expensive and is not indicated in the majority of patients.


Testing for the CFTR Gene

The ICD-10 diagnosis code for cystic fibrosis/CFTR gene testing is Z13.228. Please see the "Genetics and Advanced Sperm Testing Costs" section of this website for more detailed information on the costs of testing if not covered by insurance.  


Health Problems Associated with CFTR Mutations


Renal Abnormalities

Because the genital duct and the renal tract have their origins in the same embryonic structure, men with congenital genital duct abnormalities are at a higher risk of having problems with kidney development as well. These problems include having a missing or atrophic (non-functioning) kidney on one side. The incidence of congenital renal problems in men with CBAVD is 10–20 percent, and in men with CUAVD it is 30 percent.

All men with a suspected genital duct development abnormality should have a renal ultrasound to check for the presence of renal anomalies.


Lung Problems

Most men with CBAVD do not have lung problems. However, since the various CFTR gene mutations have different levels of severity, it results in a spectrum of disease. Some CBAVD patients may have some chronic mild lung or sinus problems that can have an impact on their long-term health. CBAVD patients should be asked about a history of such problems as recurrent sinusitis, bronchitis, and pneumonia, and should be followed routinely by their primary care physicians.


Sperm Production

Most men with CBAVD have normal sperm production. However, about 10 percent of these men do have problems making sperm. Therefore, FSH testing is recommended prior to sperm extraction procedures (see “Hormone Testing and Interpretation" section for more information).


Inguinal Hernia

The incidence of inguinal hernias is higher in men with CBAVD (5 percent) than it is in the general population (1.5 percent).


Historical Anecdote: Whey Are CFTR Mutations So Common?

CFTR gene mutations are relatively common in the population because of the survival advantage they gave to people in the distant past. Carrying just one copy of the CFTR gene mutation decreases the amount of fluid loss that a person suffers during diarrhea, and therefore increased their chance of surviving severe diarrheal diseases (such as cholera) in a time before modern medical management. These illnesses were a significant cause of death in the past, and continue to be in some countries.

Kallmann Syndrome


Kallmann syndrome (KS) is a genetic abnormality that usually involves a mutation of the KAL-1 gene. Typically only men are clinically affected, because it is an X-linked condition and they have just one X chromosome; women are usually just carriers, because they have two X chromosomes, and if the other X chromosome is normal, they do not develop symptoms. Men with KS have no GnRH secretion from the hypothalamus area of the brain, which in turn leads to no FSH and LH production by the anterior pituitary gland. Men with KS are therefore usually azoospermic, with low FSH, LH, and testosterone levels. Men with KS are most often diagnosed as teenagers, when they undergo an evaluation because of delayed onset of puberty.


Kallmann syndrome can be associated with other abnormalities as well, including:

      1) Facial/cranial asymmetry

      2) Renal abnormalities or failure to develop

      3) Cryptorchidism

      4) Cleft palate

      5) Gynecomastia

      6) Color blindness

      7) Cerebellar dysfunction

      8) Congenital deafness

      9) Neurologic abnormalities


A definitive diagnosis of KS can be difficult, as it is not detected by normal karyotype testing. Specific testing for the KAL-1 gene on the X chromosome can be performed, and can provide a diagnosis if the entire gene is absent. However, multiple genes on several different chromosomes may also play a role in the development of Kallmann syndrome, and the absence of these genes (or only small abnormalities of the KAL-1 gene) may not be detected with KAL-1 gene testing. Genetic counselors should be involved in making the decision about testing for KS.


Management of Kallman Syndrome

The primary fertility issue in men with Kallmann syndrome is a lack of gonadotropins (FSH and LH). These men typically respond well to LH and FSH replacement therapy. Treatment is generally started with HCG. If sperm have not returned after six months of therapy, then FSH is added. On this regimen, sperm can be expected to return in 90 percent of men with KS. Despite the fact that in about 70 percent of these men sperm counts do not reach normal levels, most are able to conceive naturally or with use of low-tech treatments such as IUI. Genetic counseling is recommended for couples prior to undergoing fertility treatments using the man’s sperm.

Other Genetic Abnormalities


46 XX Syndrome

Men with a 46 XX karyotype have had part of the Y chromosome (called the sex-determining region Y gene, or SRY gene) translocated to the X chromosome. The SRY gene is responsible for the development of male anatomy and appearance. However, the rest of the genes on the Y chromosome that are responsible for sperm production (including the AZF region) are missing. Men with 46 XX are therefore completely azoospermic, and they typically have small, firm testicles with high FSH and low testosterone levels. Attempted sperm extractions with methods such as mTESE will not be successful in finding sperm, since the entire AZF region of the chromosome is missing. For these men, adoption, donor sperm, or donor embryos are the only options for having children.


47 XYY Syndrome

The 47 XYY karyotype occurs in approximately one in a thousand live male births. It is associated with increased height, but past theories of an association with aggressive and antisocial behavior have been mostly dismissed. Some men with 47 XYY are fertile, but there are high rates of severe oligospermia and azoospermia in this population. Lab values typically show normal testosterone and LH levels but high FSH levels. Most of the sperm produced by these men are genetically normal, but genetic counseling and preimplantation genetic diagnosis (PGD) are recommended if the couple wishes to decrease the chance of passing on the same genetic abnormality to offspring.

Preimplantation Genetic Diagnosis (PGD) and Preimplantation Genetic Screening (PGS)


PGD and PGS are methods genetic evaluation of embryos during IVF.  Essentially, while still developing in the lab, the embryos are biopsied and the cells sent off for genetic analysis.  There are 2 primary strategies employed with these techniques:

#1) To look for specific genetic disorders for which one of the parents is a carrier (PGD)

#2) To evaluation for the presence of a number of more commonly found genetics mutations that can arise de novo and that can cause

pregnancy loss (PGS)

To make things even more confusing, the terminology is currently in the process of changing:

Screen Shot 2019-01-11 at 3.30.39 PM.png

For the purpose of this website, we will continue to use the old names of PGD and PGS, but just know that the fertility community is moving towards routine use of the new nomenclature.

Preimplantation Genetic Diagnosis (PGD)

PGD is a technique that can be used to genetically evaluate embryos during an IVF cycle before these embryos have been transferred into the woman’s uterus. Traditionally, PGD has been used in conjunction with IVF to see if a developing embryo in the lab is harboring certain single-gene abnormalities. PGD was first introduced in 1990 and has primarily been used in couples with known heritable genetic problems.


Common diseases for which PGD is used include:

      1) Sickle cell anemia

      2) Cystic fibrosis

      3) Beta thalassemia

      4) Myotonic dystrophy type I

      5) Huntington’s disease

      6) Familial adenomatous polyposis


Traditionally with PGD, once the embryo reached the eight-cell stage on day 3 (when it is called a blastomere), one cell would be removed and sent for genetic evaluation. The results of the genetic testing would be available by day 5, when blastocyst transfer of those embryos that did not harbor the genetic abnormalities in question would be done.


PGD has several downsides:

      1) There is some evidence that embryo biopsy may modestly decrease IVF success rates

      2) The woman must generate a sufficient number of eggs to have enough day-3 embryos to biopsy; she also must have enough

                 progressing day-5 embryos to transfer, which may be difficult in women with decreased ovulatory reserve.

      3) Embryo mosaicism (in which different cells in the same embryo have different genetic makeups) can decrease the accuracy of

                 finding an abnormality when only one cell is tested.


To address the problem of embryo mosaicism, multicellular biopsies (called trophoectoderm biopsies) are now often performed on the day-5 or day-6 embryo (blastocyst). However, a trade-off is that the embryos must then be frozen (vitrified) while waiting for the results of the genetic testing, and some experts think this embryo cryopreservation can modestly decrease IVF success rates, although not all specialists agree.

Generally, PGD is thought to be about 90 percent accurate. Due to the 10 percent error rate, fetal testing such as chorionic villus sampling (done at 10–14 weeks) or amniocentesis (at 15–22 weeks) is also recommended for prenatal diagnosis.

The cost of PGD is usually in the range of an extra $3,000 to $6,000 and is typically not covered by insurance, even if a couple has insurance coverage for IVF.


Gender Balancing

Gender balancing involves performing PGD for the primary purpose of choosing the sex of a child. Most IVF laboratories do not routinely offer gender balancing.


Preimplantation Genetic Screening (PGS)

Similar to PGD (see above), PGS involves the biopsy of developing embryos during IVF.  However, instead of looking for a specific genetic disease, PGS screens for genetic abnormalities in all 23 twenty-three chromosome pairs.  The issue is that a large number of embryos are genetically abnormal and will not implant and establish a successful pregnancy.  Studies have shown that up to 40%  percent of embryos are abnormal in women less than 35 thirty-five years of age, and with this number increasinges to 75%  percent in women who are 40 years forty and older.  The theory of behind PGS is that if only genetically normal embryos are transferred, then the implantation and pregnancy rates will hopefully improve.

Traditionally, PGS has been used for certain “high- risk” couples, including those in which the woman is older, those who have experienced :

            1) Advanced maternal age

            2) Recurrent IVF failure

            3) Recurrent pregnancy loss.


However, lately there has been a shift of toward using this technology in younger, lower- risk couples in order to try and increase pregnancy rates.  Currently, the stance of the American Society of Reproductive Medicine holds the position that (ASRM) state that the available studies do not support the use of PGS to try and to improve pregnancy rates and decrease miscarriage rates with IVF.  However, technical advances keep bringing down the price for PGS down as well as increasing the speed at which this testing can be performed (i.e. which means that it is no longer necessary not need to freeze the embryos while the lab awaits the results). which This is prompting more labs to look into this technology as a way to increase the success rates of their IVF cycles.