Indication for PGD

  1. Advanced maternal age :
  2. Women of advanced maternal age (>35years) are at a higher risk of producing aneuploid embryos, resulting in implantation failure, higher risk of miscarriage or chromosomally abnormal child birth.

  3. Recurrent miscarriage :
  4. Chromosomal abnormality is one of the most common causes of recurrent first trimester abortions. Either one of the couple or both may be a carrier of a balanced translocation or an aneuploid mosaic.

  5. Repeated IVF/ICSI failure cycles :
  6. Couple with repeated unsuccessful IVF cycles should be evaluated for the presence of chromosomal abnormality.

  7. Unexplained infertility :
  8. One of the reason for unexplained infertility in either of the partners may be a carrier of a translocation or an aneuploid mosaicism

  9. Male Factor infertility :
  10. Some of the male factor infertility disorders are due to chromosomal abnormality i.e aneuploidy or a structural chromosomal abnormality. Men carrying a balanced translocation are at risk of producing abnormal sperm.

  11. Y-Chromosome deletions :
  12. Y chromosome deletions are found in ~ 5-20% of men with a very low sperm count,. These deletions do not appear to cause any genetic disease, but decrease the chances of fertility.

  13. Genetic Causes :
  • Aneuploidy : Too many or too few chromosomes , it is always associated with physical and/or mental developmental problems. It occurs at the time of fertilization
  • Trisomy : Instead of a pair, 3 chromosomes are present
  • Monosomy : Instead of a pair single chromosome is present.
  • 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 implantation and undergo spontaneous abortion.
    But chromosomes involving 13,18, 21, X or Y, embryo may implant and carry to term. eg

  • Down syndrome – Trisomy -21 Three copies of chromosome
  • Patau syndrome – Trisomy – 13
  • Edward syndrome – Trisomy – 18
  • Klinefelter syndrome – presence of an extra sex chromosome 47, XXY
  • Turner Syndrome – missing a sex chromosome 45 , X

Structural Chromosome Abnormalities :

Translocations :

In Translocations a piece of chromosome go and attached to a wrong chromosome. There are two types of structural chromosome abnormalities

  • Robertsonian & Reciprocal Translocations

Robertsonaian Translocations :

A type of translocation exclusive to the acrocentric chromosomes (13,14,15,21 & 22), in which two chromosomes join at or near their centromeres . This is effectively a fusion between two chromosomes rather than an exchange of material as in reciprocal translocations. Oocyte and sperm from couple carrying Robertsonian translocation either contain balanced or unbalanced genetic material. In case of unbalanced translocation resultant embryo will have too many copies of one chromosome and too few copies of the other.

This results in too many or too few normal genes on a chromosome. It may lead to embryo death, miscarriage or live birth of an infant with substantial medical problems.

Uniparental disomy [UPD] & Robertsonain Translocations :

Genomic imprinting :

Differential expression of genes based on their parent of origin. Disrupted imprinting can give rise to birth defects testing for UPD can be done by comparing DNA from each parent to the DNA of the embryo.

Reciprocal Translocations :

It is a exchange of chromosomal material between the wrong chromosomes. If this exchange breaks a gene, person will have a genetic disease.

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. eg. Cri du chat, prader-will and Angelman’s syndrome.

Chromosome inversions :

Inversions occur when a single chromosome breaks in two places and the material is reconstituted upside down. If the chromosome breaks and does not disrupt any gene, individual with an inversion are normal but if a gene sequence is altered the individual will have a genetic abnormality. eg. Leukemia [inversion of chromosome 16].

Conditions diagnosed by PGD :

Sex – linked disorders :

Genetic disorders caused by mutations in genes on the sex chromosomes [X,Y] are called sex linked disorders. Females have two X chromosomes, One inherited from each parents. Men have one X and one Y chromosome. Genes for most sex linked disorders are located on X chromosome, usually occurs in men. As men has only one X chromosome, so a single recessive gene on that X chromosome will cause the disease. Although the Y chromosome is the other half of the XY gene pair in the men, the Y chromosome does not contain most of the genes of the X chromosome. And therefore does not protect the men.

Dominant inheritance occurs when an abnormal gene from one parent is capable of causing disease even though the matching gene from the other parent is normal. The abnormal gene dominates the outcome of the gene pair .
For eg. Rett Syndrome, Incontinentia pigmentin, pseudohyper parathyroidism, vitamin D-resistant rickets

Recessive Inheritance occurs when both matching genes must be abnormal to produce disease. If only one gene in the pair is abnormal, the disease is not manifest or is only manifest mildly. Eg. Hemophilia, fragile X-syndrome, neuromuscular dystrophies.

Carrier – Some one has one abnormal gene (No symptoms) is called a carrier. A carrier can pass this abnormal gene onto his or her children. Eg. Cystic fibrosis

Typical scenario

X- Linked Recessive disorder in women

Women with X-linked recessive disorder are rare, since women has two X-chromosomes.

Two Scenarios:

The odds of either of these two scenarios are so low that X-linked recessive diseases are some times referred to as “men only” disease, although this is not technically correct.

  1. Single Gene disorders :
  2. Single gene defects are caused by single gene abnormalities. This is called a mutation. The mutation may be present on a single chromosome of a pair or on both chromosomes of the pair. Mutations cause an error in the genetic information of the gene that alters the normal functions of the cell, due to lack of a required protein. Single gene disorders usually show a characteristic family history of a specific genetic disease. eg. Cystic Fibrosis, Sickle–cell-disease, Fragile –X, Thalassemia, and Duchenne muscular dystrophy.

    Single gene disorders are classified on the basis of whether it is autosomal recessive, autosomal dominant and X-linked.

  3. Chromosomal Disorders :
    • Variety of chromosomal rearrangements, like translocation, inversions and deletions, duplications can be detected using FISH.
    • Couple who never achieved viable pregnancy and used to have spontaneous miscarriages can have successful conception with PGD with balanced chromosomal embryos.

  4. Y-Chromosome Deletions
  5. Uniparental Disomy [UDP]

Aneuploidy and maternal age :

  • The rate of aneuploidy in embryos is greater with increased women age. The chromosomes in the oocyte are less likely to divide properly, leading to an extra or missing chromosome in the embryo.
  • The embryo with aneuploidy is less likely to carry pregnancy to term and most likely results into miscarriage.
  • Therefore using PGD to determine the chromosomal make up of embryos increases the chances of a healthy pregnancy and reduces the number of pregnancy losses and birth of affected off-spring

Table shows the chromosomal abnormality % with relation to age

Normal Embryo
Aneuploidy Embryos
Other abnormalities

One of the most frequent aneuploidies, trisomy (3 identical chromosomes present in the embryo) is trisomy of chromosome 21 , which leads to down syndrome and table shows pregnancy of down syndrome in relation to maternal age.

Age(yrs)Frequency of Fetuses with Down syndrome to normal Fetuses at 16 weeks of pregnancyFrequency of Fetuses with Down syndrome to normal Fetuses at 16 weeks of pregnancy