Principles of Medical Genetics

Principles of Medical Genetics - Code's Core

• DNA & RNA: Fundamental nucleic acids.
  • DNA (Deoxyribonucleic Acid): Double helix; A-T, G-C base pairing; stores genetic blueprint.
  • RNA (Ribonucleic Acid): Single strand; A-U, G-C pairing; involved in protein synthesis & gene regulation.
• Gene: Basic hereditary unit; DNA segment coding for a functional product (protein/RNA).
• Chromosome: Organized structure of DNA & proteins; humans have 23 pairs (46 total).
• Genome: An organism's complete set of DNA.
• Mutation: Permanent alteration in DNA sequence.
  • Point Mutation: Single nucleotide change (e.g., silent, missense, nonsense).
  • Frameshift Mutation: Insertion/deletion of nucleotides (not in multiples of three); alters reading frame.
  • Chromosomal Aberrations: Changes in chromosome number or structure.
• Key Terminology:
  • Allele: Alternative form of a gene at a given locus.
  • Locus: Specific physical location of a gene on a chromosome.
  • Genotype: Genetic constitution of an individual.
  • Phenotype: Observable characteristics resulting from genotype-environment interaction.

⭐ Single Nucleotide Polymorphisms (SNPs) are the most common type of genetic variation among people, each SNP representing a difference in a single DNA building block, called a nucleotide.

Principles of Medical Genetics - Family Lines

Pedigree analysis: Visual tool tracking genetic traits across generations. Key for pattern recognition & risk assessment.

• Autosomal Dominant (AD):
  • Vertical pattern; affects both sexes.
  • 50% risk to offspring from affected heterozygote.
• Autosomal Recessive (AR):
  • Horizontal pattern (siblings); skips generations.
  • Parents usually unaffected carriers.
  • 25% risk to offspring of two carriers. Consanguinity ↑ risk.
• X-linked Recessive (XLR):
  • Mainly males affected; carrier females.
  • No male-to-male transmission.
• X-linked Dominant (XLD):
  • Affected fathers: all daughters affected, no sons.
  • Affected mothers (heterozygous): 50% risk to offspring (any sex).
• Y-linked (Holandric):
  • Only males affected; father to all sons.
• Mitochondrial:
  • Maternal inheritance: affected mother to ALL offspring.
  • Fathers don't transmit.

⭐ Variable expressivity and incomplete penetrance can complicate pedigree analysis in Autosomal Dominant conditions.

Principles of Medical Genetics - Count & Construct

• Chromosomal Abnormalities: Deviations in chromosome number or structure.
  • Numerical Abnormalities (Aneuploidy): Gain or loss of chromosomes.
    • Trisomy: Extra chromosome (e.g., Down Syndrome - Trisomy 21).
    • Monosomy: Missing chromosome (e.g., Turner Syndrome - 45,X0).
    • Examples:
      • Down Syndrome (47,XX,+21 or 47,XY,+21)
      • Turner Syndrome (45,X0)
      • Klinefelter Syndrome (47,XXY)
  • Structural Abnormalities: Changes in chromosome structure.
    • Deletions: Loss of a chromosome segment (e.g., Cri-du-chat Syndrome - 5p deletion).
    • Duplications: Repetition of a chromosome segment.
    • Translocations: Exchange of segments between non-homologous chromosomes (e.g., Philadelphia chromosome in CML - t(9;22)).
    • Inversions: Segment reversed.
• Karyotyping: Visual analysis of chromosomes; detects numerical and large structural changes.

⭐ Robertsonian translocation is a common cause of familial Down Syndrome, involving acrocentric chromosomes (13, 14, 15, 21, 22).

Principles of Medical Genetics - Disease Detectives

• Key Diagnostic Techniques:
  • PCR (Polymerase Chain Reaction): Amplifies specific DNA segments. Used for infections, single gene disorders.
  • FISH (Fluorescent In Situ Hybridization): Visualizes specific DNA sequences on chromosomes; detects aneuploidy, deletions.
  • Microarrays (CGH, SNP): Genome-wide detection of copy number variations (CNVs) and SNPs.
  • Sequencing (Sanger, Next-Generation Sequencing - NGS): Determines exact nucleotide order.
• Prenatal Diagnosis Methods:
  • Invasive: Chorionic Villus Sampling (CVS) (10-13 wks), Amniocentesis (15-20 wks).
  • Non-Invasive Prenatal Testing (NIPT): Analyzes cell-free fetal DNA in maternal blood.
• Population Genetics:
  • Hardy-Weinberg Equilibrium: $p^2 + 2pq + q^2 = 1$ and $p+q=1$. Describes stable allele/genotype frequencies.
• Genetic Counseling Essentials:
  • Providing information, risk assessment, discussing implications, informed consent, psychosocial support.

⭐ Trinucleotide repeat expansion disorders (e.g., Huntington's, Myotonic Dystrophy) often show anticipation - increased severity/earlier onset in successive generations.

High‑Yield Points - ⚡ Biggest Takeaways

• Autosomal Dominant: Vertical transmission; 50% offspring risk; variable expressivity.
• Autosomal Recessive: Horizontal transmission; 25% offspring risk (carrier parents); consanguinity ↑ risk.
• X-linked Recessive: Affects males; no male-to-male transmission; carrier females.
• Mitochondrial Inheritance: Maternal transmission to all offspring; heteroplasmy causes variability.
• Penetrance: All-or-none expression; Expressivity: Severity variation.
• Hardy-Weinberg principle predicts genotype frequencies from allele frequencies in populations.
• Pleiotropy: One gene, multiple traits. Locus heterogeneity: Different genes, same disease.