MED 106: Genetic - Mosaicism and Trisomies

Genetic Pathology of IVF

• Infertility is defined as the inability of a couple to conceive within 1 year, with primary infertility applying to those who have never conceived, and secondary infertility to those who have conceived at some time in the past.
• Sterility implies an intrinsic inability to achieve pregnancy, whereas infertility implies a decrease in the ability to conceive and is synonymous with subfertility.
• Fecundity is the probability of achieving a live birth in 1 menstrual cycle, and fecundability is the likelihood of conception per month of exposure.

General Aspects of Infertility

• The prevalence of women diagnosed with infertility is approximately 13%, with a range from 7 to 28%, depending on the age of the woman.
• The incidence of primary infertility has increased, with a concurrent decrease in secondary infertility, likely due to social changes such as delayed childbearing.
• 10-15% of couples with regular intercourse will have difficulties in conceiving, and 1-2% of couples will be sterile.
• The number of infertility visits has increased over the past decades, partly due to couples voluntarily delaying childbearing in favor of establishing careers, which may experience an age-related decline in fertility.

Causes of Infertility

• Both male and female partners can have causes for infertility.
• Female causes include:
  • Tubal diseases
  • Ovulatory disturbances
  • Endometrial diseases
  • Endometriosis
  • Genetic diseases
  • Unexplained infertility
• Male causes include:
  • Low sperm count, motility, or morphology
  • Azoospermia
  • Genetic diseases
  • Ejaculatory disturbances
  • Impotence
  • Hormonal disturbances

IVF (In Vitro Fertilization)

• First performed in 1978
• Ovum at ovulatory stage is collected by needle after hyperstimulation of the ovaries
• Sperm is collected from the male partner, or extracted directly from the testis by operation (mTESE)
• Sperm and ovum are fertilized by two ways: IVF (putting sperm and ovum in the same place) or ICSI (injecting one sperm into the ovum)
• 3-5 days after fertilization, the embryo is transferred to the uterine cavity

Genetic Diseases Treated by IVF+PGD

• Single gene disorders
• Translocations, inversions, and insertions (chromosome structural defects and recombinations)
• Mosaicism
• Aneuploidy screening

Single Gene Disorders

• Inherited disorders caused by a faulty gene that can be passed from parent to child
• Faulty genes can occur on any of the chromosomes
• Examples include:
  • Thalassemias
  • Muscular Distrophies
  • Genetic metabolic diseases
  • Cystic Fibrosis

Chromosome Structural Defects

• Inversions: a chromosome rearrangement in which a segment of a chromosome is reversed end to end
• Two types of inversions: paracentric and pericentric

Mosaicism

• A condition in which a single organism possesses more than one genetic line as a result of genetic mutation
• Various genetic lines result from a single fertilized egg
• Can result from mechanisms including chromosome nondisjunction, anaphase lag, and endoreplication
• Somatic mosaicism is not generally inheritable as it does not affect germ cells

Aneuploidy Screening

• The risk of having a child with an aneuploidy increases as a woman ages
• Mostly, aneuploidies are unpredictable
• Trisomy is the most common aneuploidy, with an extra chromosome
• Examples include:
  • Down syndrome (trisomy 21)
  • Patau syndrome (trisomy 13)
  • Edwards syndrome (trisomy 18)
• Monosomy is another type of aneuploidy, with a missing chromosome
• Examples include Turner syndrome, in which a female has a missing or damaged X chromosome