Inherited Genetic Disorders
Family History · Dominant · Recessive · X linked · Abnormal Chromosome Numbers · Structural Chromosome Abnormalities
Single gene defects are caused by single gene abnormalities. This is called a mutation. The mutant may be present in a single chromosome of a pair or on both chromosomes of the pair. In some cases the mutation can be in mitochondrial DNA. Mutations cause an error in the genetic information of a gene that alters the normal function of a cell. Gene mutations can alter the cells function due to absence of a required protein. Single gene disorders usually show a characteristic family history of a specific genetic disease. Examples include Cystic fibrosis, Sickle cell disease, Fragile X, Thalassemia, and Duchenne muscular dystrophy.
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Family History
PGD is recommended for families with a history of a specific genetic disease. Using polymerase chain reaction, fluorescent PCR and DNA sequencing, the scientists in our PGD laboratory can examine each developing embryo to identify the absence or presence of these specific genetic disorders. As a result, only those embryos free of genetic disease will be transferred to the patient’s uterus so as to increase the chance of conception and ultimately a healthy baby.
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Single gene disorders are categorized depending upon whether the gene is located on the X chromosome on an autosome or whether the gene is dominant or recessive. These classifications include autosomal recessive, autosomal dominant and X-linked.
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Dominant Disorders
For a dominant disorder, one only needs to have the abnormal DNA sequence on one chromosome. If that mutation is passed on to the embryo, the embryo will be affected with that genetic disease. One example of an autosomal dominant disorder is Myotonic dystrophy.
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Recessive Disorders
Recessive disorders require that the mutation be present on both chromosomes of the chromosomal pair. If one only has the mutation on one chromosome, the individual is normal but carries the mutation in his cells and is called a carrier. The fertilization of an egg from carrier parents may result in an embryo having the mutation on both chromosomes of the chromosome pair and the embryo therefore being affected with that genetic disease. For example, Cystic Fibrosis (CF) is a common autosomal recessive genetic disorder that primarily affects the lungs of CF patients. The CF mutation affects a protein within the cell that reduces the cell’s ability to function properly. This results in a build up of mucous within the lungs, lung dysfunction and possible death.
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X-linked Disorders
X-linked disorders are due to mutations of genes on the X chromosome and have different patterned inheritance due to their transmission on a sex chromosome and whether the embryo is male or female. Examples of X-linked diseases are the Fragile X syndrome and Duchenne muscular dystrophy.
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Abnormal Chromosome Numbers: Aneuploidy
The most common type of chromosome abnormality is having too many or too few chromosomes. This is called aneuploidy. Aneuploidy is always associated with physical and/or mental development problems. The condition at birth is directly related to the type of chromosome abnormally delivered to the embryo at the time of conception.
Having an extra chromosome is called trisomy and a missing chromosome is monosomy. If the egg 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's syndrome (trisomy 21) is the presence of three copies of chromosome 21.
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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).
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Figure: Fluorescence in situ hybridization
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Patau syndrome (trisomy 13) is the presence of three copies of chromosome 13. Edward syndrome (trisomy 18) has 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 missing a sex chromosome (45,X). Embryos affected with Klinefelter syndrome or Turner syndrome may also spontaneously abort.
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Structural Chromosome Abnormalities
Translocations
There are two types of structural chromosome aberrations, Robertsonian and reciprocal translocations. Translocations occur when pieces of a chromosome are attached to the wrong chromosome.
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Robertsonian
Robertsonian translocations are 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 genetic material (be balanced) or contain an unbalanced amount of genetic material (unbalanced). If sperm or an 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.
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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. Disrupted imprinting can give rise to birth defects. The fetus can have physical abnormalities and intrauterine growth retardation. Since embryos with UPD of some chromosomes are at risk for medical complications, UPD testing may be considered. Testing can be done for UPD by comparing the DNA from each parent to the DNA of the embryo.
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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, the amount of genetic material present is the same as with normal individuals, the person is balanced and normal. However, the sperm or eggs of these individuals can carry the reciprocal translocation chromosome and are at risk of producing an embryo with an abnormal amount of genetic material. As with Robertsonian translocations, the couple is at increased risk for repeated miscarriages, repeated unsuccessful IVF cycles or the birth of a child with a genetic disorder.
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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 attached to chromosome 20 (derivative 20).
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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. Cri d Chat, Prader-Willi and Angelman’s syndrome are examples of genetic disease caused by a chromosomal deletion.
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Figure: Genetic material C and D are lost from the chromosome from the chromosome.
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Chromosome Inversions
Inversions occur when a single chromosome breaks in two places and the material in-between is reconstituted upside down. If the chromosome breaks and does not disrupt any gene, people with inversion are 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 and/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 can fail to grow, miscarry, or be liveborn with substantial medical problems.
Figure: The chromosome breaks in two places and is reformed upside down.
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