Genetic Disorders & Counseling

• The topic is genetic disorders, genetic testing, prenatal diagnosis, genetic counseling, and preimplantation genetic diagnosis
• Probabilities of recurrence can be determined from the mode of inheritance (AD, AR, XD, XR).
• Multifactorial diseases follow multifactorial inheritance patterns.
• Recurrence risk is determined by maternal age of 35 or older, family history, abnormalities seen on ultrasound, and worrisome screening test results.

Genetic Counseling

• Genetic counseling is a communication process addressing human problems linked to the occurrence or risk of genetic disorders within a family.
• Trained professionals assist individuals or families to:
  • Comprehend medical facts, including diagnosis and available management.
  • Appreciate heredity's role and recurrence risk.
  • Understand alternatives.
  • Choose appropriate actions based on risk, family goals, and ethical/religious standards.
  • Adjust to the disorder or recurrence risk.
• The process helps people understand and adapt to medical, psychological, and familial implications and integrates:
  • Interpretation of family and medical histories.
  • Education about inheritance, testing, management, prevention, resources, and research.
  • Counseling for informed choices and adaptation.
• Seek genetic counseling if:
  • There's a personal or family history of a condition or birth defect.
  • Pregnancy is planned after 35.
  • A child has a genetic disorder.
  • There have been multiple pregnancy losses
  • Ultrasound or screening tests suggest possible problems

Principles of Genetic Counseling

• Bayes' theorem is a statistical principle used to analyze genetic information.
• Prior probability: likelihood of an event before new information.
• Conditional probability: likelihood of an outcome based on previous outcomes.
• Joint probability: product of prior and conditional probabilities.
• Posterior probability: likelihood of an individual carrying a mutant gene

Ethical Aspects of Genetic Counseling

• Confidentiality
• Informed consent
• Beneficence and nonmaleficence
• Cultural influences
• Non-directiveness
• Utility of genetic information
• Distributive and social justice

Types of Prenatal Diagnosis

• Prenatal diagnosis focuses on genetic testing, aiming to give at-risk families information for informed choices during pregnancy
• Benefits include reassurance when results are normal, risk information for couples, psychological preparation, healthcare planning, and information about pregnancy termination options.
• Both screening and diagnostic tests can be done prenatally
• Different types of prenatal diagnosis
• Ultrasonography
• Amniocentesis
• Chorionic villus sampling
• Fetal blood cells in maternal blood
• Cordocentesis, or percutaneous umbilical blood sampling (PUBS)
• Maternal serum alpha-fetoprotein
• Maternal serum beta-HCG
• Maternal serum unconjugated estriol
• Pregnancy-associated plasma protein A
• Inhibin A
• Non-invasive prenatal screening (NIPS)

Amniocentesis

• Amniocentesis involves withdrawing amniotic fluid and can diagnose many genetic diseases around 16 weeks post-LMP
• Elevated amniotic a-fetoprotein indicates a neural tube defect.
• Fetal loss risk is approximately 1/300 to 1/500 above background.
• Earlier amniocentesis may increase fetal loss rates.
• Risk increase is 0.2% to 0.3% above background.
• Factors that indicate amniocentesis:
  • Maternal age >35 years
  • Previous child with chromosome abnormality
  • History of structural chromosome abnormality in one parent
  • Family history of diagnosable genetic defect
  • Increased risk of neural tube defect
  • Abnormal quadruple screen

Chorionic Villus Sampling (CVS)

• CVS is performed earlier than amniocentesis (10-11 weeks post-LMP).
• It can be done transcervically or transabdominally.
• Fetal loss risk is about 1% to 1.5%.
• Confined placental mosaicism can confuse diagnosis.
• CVS before 10 weeks may increase limb deficiency risk.
• Fetal loss rate is about 0.5% to 1% above background

Fetal Tissue Sampling - Cordocentesis (PUBS)

• Cordocentesis is another method of fetal tissue sampling

Ultrasonography

• Useful to reveal fetus with normal spinal column
• Useful to reveal ultrasound result for a fetus with a meningomyelocele

Maternal Serum Screening

• Maternal serum alpha-fetoprotein (MSAFP) levels vary in mothers carrying fetuses with Down syndrome, normal fetuses and open spina bifida, and this is a screening approach for abnormalities:
  • The level of MSAFP will be somwhat lower in the fetus with Down syndrome
  • The level of MSAFP wil be substantially elevated in the fetus has an open spina bifida
• MSAFP increases prenatal detection of abnormalities;
• It has virtually no risk but lower sensitivity and specificity for NTDs
• Additional markers in the second trimester increase sensitivity.
• Screening for Down syndrome, trisomy 13, and trisomy 18 can be done in the first trimester.

Non-Invasive Prenatal Screening (NIPS)

• NIPS is a prenatal screening can be done after the 10th week of pregnancy
• Cell-free DNA (cfDNA) is evaluated for mutations/aneuploidy using high-throughput sequencing.
• The procedure entails no risk of fetal loss and has greater specificity than other screening procedures

Preimplantation Genetic Diagnosis

• Preimplantation genetic diagnosis (PGD) identifies unaffected embryos before implantation of polar bodies, blastomeres, or blastocyst cells
• Only unaffected embryos are implanted
• IVF-derived embryos can be diagnosed by removing a single cell from the eight-cell stage.
• The DNA is then amplified using PCR for genetic diagnosis
• Pregnancy termination is not required
• There is a possibility of diagnostic error because of PCR amplification from a single cell.