GENETIC DISORDERS SAQs EXAMINATION

# GENETIC DISORDERS - 30 KEY SHORT ANSWER QUESTIONS **Comprehensive coverage: Mutations, Mendelian Disorders, and Inheritance Patterns** --- ## SECTION A: INTRODUCTION & APPLICATIONS OF GENETICS (4 Questions) **1. What is the lifetime frequency of genetic disease and why is it higher than commonly appreciated?** **Answer:** - Lifetime frequency: **670 per 1000 individuals** - Higher than appreciated because includes:"Classic" genetic disorders (single gene, chromosomal) - Cardiovascular diseases with genetic components - Disorders of immunity - Cancers (genetic mutations in somatic cells) - Variable expressivity (mild/hidden presentations) - **~50% of early pregnancy miscarriages** have chromosomal abnormalities - **~5% of individuals <25 years** develop serious disease with significant genetic component - Many mild genetic disorders remain undiagnosed **2. Explain the human genome composition and genetic diversity.** **Answer:** **Genome composition:** - Approximately **30,000 genes** in human genome - **<2% code for proteins** (protein-coding genes) - **>50% are repetitive sequences** of unknown function - Includes regulatory sequences, introns, non-coding RNAs **Genetic diversity:** - Humans share **99.9% of DNA sequence** - **0.1% difference = ~3 million base pairs** - This 0.1% accounts for:Individual variations - Disease susceptibility - Physical characteristics - Drug responses - Ethnic diversity **3. Compare functional cloning and positional cloning approaches.** **Answer:** **Functional (Classic) Cloning:** - Start with: Known affected protein/clinical phenotype - Steps:Identify abnormal protein through clinical/biochemical studies - Isolate and clone normal gene - Determine molecular changes in disease - Example: Sickle cell anemia (abnormal hemoglobin identified first) **Positional (Candidate Gene) Cloning:** - Start with: Chromosome location of disease - Steps:Map disease phenotype to chromosome location (linkage analysis) - Clone multiple DNA pieces from that region - Identify aberrant proteins from mutated genes - Work backwards from location to function - Example: Huntington disease (location found before gene function known) **4. Describe four major applications of genetics in medicine.** **Answer:** **1. Molecular basis of human disease:** - Understanding disease mechanisms at genetic level - Both approaches: functional and positional cloning **2. Production of biologically active agents:** - Insert genes into bacteria/tissue culture cells - Examples: TNF receptor, tissue plasminogen activator, growth hormone, erythropoietin, insulin **3. Gene therapy:** - Transfer of somatic cells with normal genes - Treat genetic diseases at source - Ethical considerations: benefits vs risks **4. Disease diagnosis:** - Molecular probes for genetic diseases - Prenatal diagnosis - Carrier detection - Diagnosis of infectious diseases (pathogen DNA detection) - Personalized medicine approaches --- ## SECTION B: TYPES AND CATEGORIES OF MUTATIONS (7 Questions) **5. Define mutation and distinguish between germline and somatic mutations.** **Answer:** **Mutation:** - Permanent change in DNA sequence - Can affect single base pairs to large chromosomal segments **Germline mutations:** - Occur in germ cells (sperm/egg) - Transmitted to progeny - Present in all cells of offspring - Cause inherited/hereditary diseases - Examples: Hemophilia, cystic fibrosis, sickle cell disease **Somatic mutations:** - Occur in body (somatic) cells - NOT transmitted to progeny - Present only in affected tissue/cell lineage - Cause: cancers, some congenital malformations - Examples: Most cancers, some birthmarks **6. Describe the three major categories of mutations.** **Answer:** **1. Genome mutations:** - Affect whole chromosome number - **Monosomies:** Loss of one chromosome (e.g., Turner syndrome 45,X) - **Trisomies:** Gain of one chromosome (e.g., Down syndrome, trisomy 21) - Result from nondisjunction during meiosis **2. Chromosome mutations:** - Rearrangement of genetic material - Visible structural changes under microscope - Types: deletions, duplications, inversions, translocations - Example: Philadelphia chromosome t(9;22) in CML **3. Gene mutations:** - Changes within individual genes - May involve:Single base pair (point mutations) - Small deletions/insertions - Partial or complete gene deletion - NOT visible cytogenetically **7. Explain point mutations and their three types.** **Answer:** **Point mutations:** Substitution of single nucleotide base **1. Missense mutations:** - Change one amino acid to another - **Conservative:** Similar amino acid (minimal effect) - **Non-conservative:** Different amino acid properties (significant effect) - Example: Sickle cell anemia (glutamic acid → valine) **2. Nonsense mutations:** - Change amino acid codon to **stop codon** (UAA, UAG, UGA) - Premature termination of translation - Truncated, non-fun