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• Genetic counseling involves a communication process where people and their families get advice about genetic disorders, risk assessments, and testing options.

Key Aspects of Genetic Counseling

• Risk assessment: Estimating the chance of a genetic condition occurring.
• Education: Explaining inheritance patterns, genetic testing, and medical options.
• Counseling: Providing emotional and ethical support.

Ethical Principles in Genetic Counseling

• Autonomy: Patients can make their own choices about genetic testing and disclosure.
• Beneficence: Counselors must act in the patient's best interests.
• Non-maleficence: Genetic information should be communicated carefully to avoid unnecessary distress.
• Justice: Ensuring fair access to genetic counseling services.

Confidentiality vs. Duty to Warn

• Confidentiality: A patient's genetic information must be protected unless they consent to share it.
• Duty to Warn: If a genetic condition can seriously harm family members, legal guidelines may allow disclosure without patient consent.

Key Legal Cases & Guidelines

• Pate v. Threlkel: Doctors must inform patients about genetic risks to enable them to warn relatives.
• Safer v. Estate of Pack: Doctors may need to take extra steps to inform relatives if a serious risk exists.
• ASGH Guidelines: Disclosure without consent is allowed only if the condition is life-threatening and preventable.

Misattributed Paternity & Ethical Dilemmas

• Misattributed paternity: When genetic testing reveals that the presumed father is not the biological father.

Ethical Conflict

• Should the counselor disclose this information?

Option 1: Tell the Father

• Truth-telling (Autonomy).
• The father needs to know for legal and emotional reasons.
• Ensuring medical history accuracy for the child.

Option 2: Do NOT Tell the Father

• Mother's right to confidentiality.
• Disclosure could cause significant family harm (Non-Maleficence).
• Professional guidelines do not recommend disclosing without the mother's consent.

Y Chromosome & Sex Determination

• XX = Female, XY = Male in mammals.
• The SRY gene on the Y chromosome is the master switch for male development.

Testis Development (Male)

• SRY activates SOX9, forming Sertoli cells.
• Sertoli cells organize testis cords and suppress ovarian development by inhibiting β-catenin.
• Sertoli cells produce AMH (Anti-Müllerian Hormone), causing Müllerian duct degeneration and preventing uterus formation.
• Leydig cells produce testosterone, promoting Wolffian duct development, which forms male reproductive organs.
  • Epididymis (sperm storage).
  • Vas deferens (sperm transport).
  • Seminal vesicles (semen fluid production).
• 5a-Reductase converts testosterone into DHT forming external male genitalia.
  • Penis
  • Scrotum
  • Prostate Gland

Ovary Development (Female)

• No SRY Gene Activation: Bipotential gonads do not receive the male-determining signal.
• WNT4 and RSPO1 (key signaling molecules) are expressed, activating β-catenin, which is crucial in ovarian development.
• β-catenin blocks SOX9, preventing Sertoli cell formation and blocks testis development.
• Granulosa cells support ovarian follicles.
• No Anti-Müllerian Hormone (AMH) production causes the Müllerian ducts to remain and develop into:
  • Fallopian Tubes
  • Uterus
  • Upper Vagina
• No testosterone is produced, hence Wolffian ducts degenerate.

Sex Reversal: How It Happens

• Sex reversal occurs when an individual has chromosomes of one sex but develops characteristics of the opposite sex.

Causes of Sex Reversal

• SRY Gene Mutations can cause an XY individual to develop as female.
• SOX9 Overexpression can cause an XX individual to develop male characteristics.
• Androgen Insensitivity Syndrome (AIS) in 46,XY individuals results in them developing female traits due to a lack of response to testosterone.
• 5a-Reductase Deficiency in XY individuals causes ambiguous genitalia at birth.

Mitochondrial DNA & Disease Prevention

• Mitochondrial DNA (mtDNA) is inherited only from the mother because sperm mitochondria are destroyed after fertilization.
• Mutations in mtDNA cause energy production disorders.

Mitochondrial Diseases & Treatments

• Prevent mtDNA diseases by replacing faulty mitochondria via mitochondrial replacement therapy (MRT).

Common Mitochondrial Disorders, Causes & Effects

• Leigh Syndrome
  • Cause: mtDNA mutations affecting ATP production
  • Effects: Neurological decline, muscle weakness, respiratory failure.
• MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes)
  • Cause: mtDNA mutations affecting energy metabolism
  • Effects: Muscle weakness, strokes, seizures, lactic acid buildup.
• Kearns-Sayre Syndrome
  • Cause: Large-scale mtDNA deletions
  • Effects: Progressive muscle weakness, vision loss, heart problems.
• LHON (Leber's Hereditary Optic Neuropathy)
  • Cause: mtDNA mutations affecting nerve cells
  • Effects: Sudden vision loss, primarily in males.

Pronuclear Transfer (PNT)

• Performed after fertilization (zygote stage).
• This technique is cheaper with higher success rates.
• It carries a higher risk of mutant mtDNA carryover.
• It is more controversial because the original embryo gets discarded.

Egg Collection & Fertilization Steps

• The mother's egg is fertilized by the father's sperm, creating a zygote.
• A donor's egg is also fertilized with sperm to create another zygote having healthy mitochondria.

Nuclear Transfer Steps

• The nuclear DNA is removed from both embryos.
• The mother's nuclear DNA is inserted into the donor embryo.
• The reconstructed embryo is allowed to develop, then implanted into the mother's uterus.
• The baby has nuclear DNA from the parents, and has mitochondria from the donor

Spindle Transfer (MST)

• Performed before fertilization (oocyte stage)

Steps

• Nuclear DNA is extracted from the mother's egg.
• It is then transferred into a donor egg that contains healthy mitochondria.
• The egg is then fertilized with sperm.
  • This costs more and requires more care with manipulation.
  • It minimizes mutant mtDNA carryover.
  • This is less controversial as it does not involve destroying an embryo.

MITO-Porter System

• The MITO-Porter system is a nanotechnology-based drug delivery system that targets mitochondria to treat diseases by using liposomal carriers to deliver healthy mtDNA into diseased cells.
• This is still experimental but could be a potential cure for mitochondrial diseases.

Other Potential Mitochondrial Treatments includes

• Gene Therapy to insert functional mtDNA into affected cells.
• Stem Cell Therapy to use stem cells to create healthy mitochondria.

Exercise and Diet

• Helps improve mitochondrial function.

Antioxidant Therapy

• Reduces oxidative stress in mitochondria.

Ethical Concerns with Mitochondrial Replacement Therapy include

• "Three-Parent Baby" Controversy as MRT results in a child with DNA from three people.
• Long-Term Effects Unknown because MRT is a new procedure.
• Embryo Modification because some people worry that MRT is a step toward genetic engineering or designer babies.
• Religious Views: The embryo manipulation is opposed by faith due to concerns about altering natural conception.

Romanov Case Study

• To confirm their identities, Romanov family who was executed, had scientists use mitochondrial DNA (mtDNA) analysis

Mitochondrial DNA (mtDNA) Analysis

• mtDNA is inherited only from the mother, reliably identifying maternal relatives.
• Scientists compared Bone mtDNA to relatives, including Prince Philip, finding sequence matches

Heteroplasmy as Additional Evidence

• Heteroplasmy is when a person has two different mtDNA sequences in the same cell.
• Tsar Nicholas II had a unique mtDNA heteroplasmy, found in his brother Grand Duke Georgij Romanov.

Key Findings

• mtDNA was compared to living relatives (Prince Philip) confirming the Romanov family's identity.
• Heteroplasmy (variation in mtDNA sequences) confirms the identity of the remains.

Why This Case Matters

• This was the First major use of mtDNA sequencing for forensic identification.
• Showed that mtDNA can be traced through maternal lineage over centuries.

Ethical Scenarios in Genetic Testing

• A patient is BRCA1 positive but does not disclose to her daughter, which poses an ethical dilemma for the counselor

Reasons to Inform

• Daughter can get preventative measures (mastectomy, early screening).
• Serious harm prevention (Beneficence).

Reasons NOT to Inform

• Respecting patient autonomy & confidentiality.
• No legal requirement for disclosure in some cases.

Legal Perspective

• (ASHG) allows disclosure if the condition is life-threatening and the patient refuses. to inform relatives.

Legal Issues

• Confidentiality vs. Duty to Warn: Should the counselor not follow mother, to protect the the child?
• Informed Consent: Parental consent is required for testing minors.

Social Issues

• Family Stress: Child with a genetic disorder is emotionally and financially strained.
• Cultural Beliefs: Genetic testing is unnecessary or unethical across cultures.
• Stigma: A positive result leads to social discrimination.

Religious Issues

• Sanctity of Life: Genetic testing interferences with divine will.
• Reproductive Choices: Some faiths oppose abortion based on genetic test results.
• Confidentiality vs. Family Obligation: Religious traditions emphasize family responsibility over privacy.

Ethical Guidelines to Apply

• Autonomy: Respect the mother's right to refuse testing.
• Beneficence: Testing could benefit the child.
• Non-Maleficence: Ensure that withholding information does not cause harm