Chromosome abnormalities include aneuploidy and structural abnormalities. Aneuploidy is the most common chromosomal abnormality and it occurs in both eggs and sperm. Structural abnormalities in both eggs and sperm include translocations, inversions, and deletions. The transmission of a chromosome abnormality to an embryo can result in a low implantation rate, miscarriage, or the birth of a baby with a genetic disorder.

RSC’s PGD laboratory scientists use Fluorescence In Situ Hybridization (FISH) testing to help identify the absence of these specific genetic disorders in each normal developing embryo. As a result, only embryos free of genetic disease will be transferred to the patient’s uterus.

Recurrent Miscarriage
Fertile couples with repeated miscarriages should be evaluated for the presence of a chromosomal abnormality. The female or male partner may be a carrier of a balanced translocation or may be an aneuploid mosaic.
      
Unsuccessful IVF Cycles
Couples with repeated unsuccessful IVF cycles should be evaluated for the presence of a chromosome abnormality. The female or male partner may be a carrier of a balanced translocation or may be an aneuploid mosaic.
      
Unexplained Infertility
The most probable cause of unexplained infertility or history of habitual miscarriage is a chromosome abnormality. The male or female partner may be a carrier of a translocation or may be an aneuploid mosaic.
      
Aneuploidy and Advanced Maternal Age
Women 35 and older are at a higher risk of producing aneuploid embryos, which results in implantation failure, a higher risk of miscarriage or the birth of a child with a chromosome abnormality such as Down syndrome.

All of a woman's eggs are present at birth. Over time, the chromosomes within the egg are less likely to divide properly, resulting in cells with too many or too few chromosomes. Aneuploidy is also believed to be a major reason for the decrease of fertility with age. A study conducted at the Center for Preimplantation Genetic Diagnosis, under the direction of Dr. William Kearns, determined that approximately 62 percent of embryos from women of advanced maternal age might be aneuploid. Prior to attempting a pregnancy, women in this age group may wish to talk with their physician or a medical geneticist about their chances of having a child with a genetic disease and if PGD should be considered.

Table:  Women of advanced maternal age are at increased risk of producing an embryo affected with a genetic disease.

Male Factor Infertility
Approximately one-half of all infertility is caused by sperm abnormalities. Many sperm disorders are due to a chromosome abnormality such as aneuploidy or a structural chromosome abnormality. Men who carry a balanced translocation chromosome are at risk of producing sperm with a structural chromosome abnormality. A study conducted at the Center for Preimplantation Genetic Diagnosis under the direction of Dr. William Kearns determined that approximately 3 to 8 percent of sperm from normal, fertile men are aneuploid and 27 to 74 percent of sperm from men with severe infertility are aneuploid. Couples with infertility due to male factor should consider chromosome analysis of the male’s sperm prior to IVF. The photo to the right depicts aneuploid sperm.
      
Y Chromosome Deletions and Infertility
Y chromosome deletions are found in approximately 5 to 20 percent of males with a very low sperm count. These deletions appear to impair normal sperm development. While these deletions do not appear to cause any genetic disease, they appear to decrease the chance of men with a low sperm count to successfully fertilize eggs in a normal way.

Below is a list of some of the more common genetic diseases that can be detected by PGD. Any gene disorder in which the DNA base pairs or code is known, can be detected by PGD.

Genetic Causes

Abnormal Chromosome Numbers: Aneuploidy

The most common type of chromosome abnormality is the presence of too many or too few chromosomes. This is called aneuploidy. Aneuploidy is always associated with physical or mental developmental problems. The condition at birth is directly related to the type of chromosome abnormality present in the embryo at the time of conception.

The presence of an extra chromosome is called trisomy and an absent chromosome is called monosomy. If the extra or missing chromosome is an autosome (chromosomes 1 to 22), the embryo may not implant or may stop normal development soon after attaching and undergo a spontaneous abortion. If the aneuploidy involves chromosomes 13, 18, 21, X, or Y, the embryo may implant and carry to term. Down syndrome (trisomy 21) is the presence of three copies of chromosome 21.

Figure: The fertilization of a genetically abnormal egg carrying an extra chromosome 21 (tan) by a normal sperm (green) produces an embryo with Down syndrome (purple).

Figure: Fluorescence in situ-hybridization (FISH)
   
Patau syndrome (trisomy 13) is the presence of three copies of chromosome 13. Edward syndrome (trisomy 18) is the presence of three copies of chromosome 18. Other common aneuploidies seen at birth include Klinefelter syndrome and Turner syndrome. Klinefelter syndrome is the presence of an extra sex chromosome (47,XXY), whereas Turner syndrome is the absence of a sex chromosome (45,X). Embryos affected with Klinefelter syndrome or Turner syndrome may also spontaneously abort.

Structural Chromosome Abnormalities:

Translocations

There are two types of structural chromosomal aberrations; Robertsonian and reciprocal translocations. Translocations occur when pieces of a chromosome are attached to the wrong chromosome.

Robertsonian Translocations

Robertsonian translocations are the joining together of chromosomes 13, 14, 15, 21 or 22. People with a Robertsonian translocation are normal because they have the correct amount of genetic material (genes). Sperm and eggs from individuals carrying a Robertsonian translocation either contain the correct amount of genetic material (be balanced) or contain an unbalanced amount of genetic material (unbalanced). If a sperm or egg contains an unbalanced amount of genetic material and fertilization occurs, the resulting embryo will have too many copies or parts of one chromosome and too few copies or parts of the other. This results in too many or too few normal genes on a chromosome. An unbalanced state in an embryo may lead to embryo death, miscarriage, or the live birth of an infant with substantial medical problems.
      
Uniparental Disomy (UPD) and Robertsonian Translocations

Genomic imprinting is defined as the differential expression of genes based on their parent of origin. Imprinting plays an important role in early development. Birth defects such as physical abnormalities and intrauterine growth retardation can be caused by disrupted imprinting. Since embryos with UPD of some chromosomes are at risk for medical complications, UPD testing may be considered. Testing for UPD compares the DNA from each parent to the DNA of the embryo.
            
Reciprocal Translocations

Reciprocal translocations are the exchange of chromosomal material between the wrong chromosomes. If this exchange breaks a gene, this person will have a genetic disease. However, if the amount of genetic material present is the same as for normal individuals, the person is balanced and normal. However, the sperm or eggs of these individuals may carry the reciprocal translocation chromosome. They are at increased risk of producing an embryo with an abnormal amount of genetic material and are unbalanced. As is the case with Robertsonian translocations, the couple faces increased risk for repeated miscarriages, repeated unsuccessful IVF cycles, or the birth of a child with a genetic disorder.

Figure: Reciprocal translocation between chromosomes 4 and 20. This results in part of chromosome 20 attaching to chromosome 4 (derivative 4) and part of chromosome 4 attaching to chromosome 20 (derivative 20).

Chromosome Deletions

Deletions are the loss of a chromosome segment resulting in an imbalance in the number of genes present. If the deletion removes genetic material, the individual will have a genetic disorder. Some examples of genetic disease caused by a chromosome deletion include Cri du Chat, Prader-Willi and Angelman’s syndrome.

Figure: Genetic material C and D are lost from the chromosome.

Chromosome Inversions

Chromosome inversions occur when a single chromosome breaks in two places and the material inbetween is reconstituted upside down. If the chromosome breaks and does not disrupt any gene, an individual with an inversion will be normal. However, if a gene sequence is altered the individual will have a genetic abnormality. One inversion on chromosome 16 may cause a type of leukemia. The presence of an inversion chromosome during egg or sperm development can result in gametes with a duplicated or deleted portion of the inversion chromosome. This is considered an unbalanced state. Embryos with too many or too few copies of genes from this inverted chromosome may fail to grow, miscarry or are born with substantial medical problems.

Figure: The chromosome breaks in two places and is reformed upside down.

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• PGD & in Vitro Fertilization (IVF)
• PGD Procedure
• Scheduling Tests for PGD