Master Genetics
for PLAB 1

Core Concepts

**DNA & Chromosomes:** DNA forms genes on chromosomes. Humans have 46 chromosomes (23 pairs: 22 autosomal, 1 sex pair XX/XY). **Alleles:** Different gene versions. Genotype (genetic makeup) determines Phenotype (observable traits).

• **Inheritance Patterns:**
  • **Autosomal Dominant (AD):** Vertical transmission (every generation), males/females equally affected. 50% recurrence risk. E.g., Huntington's, Marfan's, Neurofibromatosis Type 1.
  • **Autosomal Recessive (AR):** Horizontal transmission (skips generations). Parents are carriers. 25% recurrence risk for siblings. E.g., Cystic Fibrosis, Sickle Cell Anaemia, Phenylketonuria. Consanguinity increases risk.
  • **X-linked Recessive (XR):** Primarily affects males. Females are carriers. No male-to-male transmission. E.g., Haemophilia A/B, Duchenne Muscular Dystrophy.
  • **Mitochondrial:** Maternally inherited. All children of affected mother affected. No paternal transmission.
• **Chromosomal Abnormalities:**
  • **Aneuploidy:** Abnormal number (e.g., Trisomy 21 Down Syndrome, Monosomy X Turner Syndrome).
  • **Structural:** Deletions, duplications, translocations.
• **Key Terms:**
  • **Penetrance:** Proportion with genotype expressing phenotype.
  • **Expressivity:** Variation in phenotype for same genotype.
  • **Anticipation:** Worsening/earlier onset in successive generations (Trinucleotide repeats: Huntington's, Fragile X).
  • **Genomic Imprinting:** Gene expression depends on parental origin (e.g., Prader-Willi, Angelman).

Clinical Presentation

• **Congenital Anomalies:** Dysmorphic features, birth defects (cardiac, renal, skeletal, clefts).
• **Developmental Delay/Intellectual Disability:** Common in many syndromes.
• **Growth Abnormalities:** Short stature, failure to thrive.
• **Family History:** Multiple affected members, recurrent miscarriages, stillbirths.
• **Specific Organ Dysfunction:**
  • Neurological: Seizures, hypotonia.
  • Haematological: Anaemia, bleeding disorders.
  • Metabolic: Inborn errors (e.g., PKU, Galactosaemia).
  • Connective Tissue: Joint hypermobility.
• Unexplained chronic illness or sudden infant death.

Diagnosis (Gold Standard)

• **Pedigree Analysis:** Detailed family history is the crucial first step.
• **Karyotyping:** Chromosome number and gross structure. Gold standard for aneuploidy (e.g., Down, Turner).
• **FISH (Fluorescence In Situ Hybridization):** Detects specific small deletions/duplications (microdeletion syndromes, e.g., DiGeorge).
• **Array CGH (Comparative Genomic Hybridization):** High-resolution detection of submicroscopic deletions/duplications. Often first-line for unexplained developmental delay/anomalies.
• **Molecular Genetic Testing (DNA Sequencing):**
  • **Sanger Sequencing:** Specific single-gene point mutations.
  • **Next-Generation Sequencing (NGS):** Panels, exome, genome sequencing for multiple genes.
• **Biochemical Testing:** For inborn errors of metabolism (e.g., newborn heel prick for PKU, MCADD, CF, hypothyroidism).
• **Prenatal Diagnosis:**
  • **NIPT (Non-Invasive Prenatal Testing):** Screening for common aneuploidies from maternal blood.
  • **Amniocentesis / Chorionic Villus Sampling (CVS):** Invasive diagnostic tests.

Management (First Line)

• **Genetic Counselling:** Essential for diagnosis, prognosis, recurrence risk, family planning, and support.
• **Multidisciplinary Team (MDT) Approach:** Involving various specialists (paediatricians, geneticists, consultants, therapists).
• **Symptomatic and Supportive Care:** No cure for most. Focus on alleviating symptoms and preventing complications.
  • Medications, surgical intervention for defects.
  • Special diets (e.g., low phenylalanine diet for PKU).
  • Rehabilitation therapies.
• **Regular Monitoring:** To track progression and manage complications.
• **Emerging Therapies:** Gene therapy for specific conditions (e.g., SMA).

Exam Red Flags