Master genetic disorders with 30 key SAQs. Covers mutations, Mendelian inheritance patterns, and clinical applications for Year 2 Molecular Genetics.
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 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-functional protein - Usually severe effect 3. Silent mutations: - Change nucleotide but same amino acid (genetic code redundancy) - No change in protein sequence - Generally no clinical effect 8. What are frameshift mutations and their consequences? Answer: Definition: - Insertion or deletion of nucleotides NOT divisible by 3 - Alters reading frame of DNA Mechanism: - Genetic code read in triplets (codons) - Insertion/deletion of 1 or 2 base pairs shifts reading frame - All downstream amino acids changed - Usually encounter premature stop codon Consequences: - Completely different amino acid sequence after mutation - Non-functional protein - Usually severe phenotype - Example: Some forms of Tay-Sachs disease Note: Deletions/insertions of 3 or multiples of 3: - Do NOT cause frameshift - Result in missing/extra amino acids - May be less severe 9. Explain trinucleotide repeat mutations and their unique characteristics. Answer: Definition: - Dynamic amplification of sequence of 3 nucleotides - Usually involves guanine (G) and cytosine (C) Unique characteristics: 1. Dynamic nature: - Degree of amplification increases during gametogenesis - Each generation may have more repeats 2. Anticipation: - Earlier onset in successive generations - More severe phenotype in offspring 3. Threshold effect: - Normal: small number of repeats - Disease: exceeds threshold number Examples: - Fragile X syndrome: CGG repeats in FMR1 gene - Huntington disease: CAG repeats in huntingtin gene - Myotonic dystrophy: CTG repeats 10. Describe mutations affecting non-coding sequences. Answer: Promoter and enhancer mutations: - Affect regulatory sequences - Interfere with transcription factor binding - Result: Reduced or absent transcription - Normal gene present but not expressed properly - Example: Some hereditary hemolytic anemias (thalassemias) Splice site mutations: - Affect intron-exon boundaries - Abnormal mRNA splicing - Aberrant proteins or no protein Effects: - May be as severe as coding sequence mutations - Difficult to detect without sequencing - Important in disease diagnosis 11. What are the three main categories of genetic disorders? Answer: 1. Diseases related to mutant genes of large effect: - Single gene (Mendelian) disorders - Autosomal dominant, autosomal recessive, X-linked - Clear inheritance patterns - Examples: Sickle cell disease, cystic fibrosis, hemophilia 2. Diseases with multifactorial (polygenic) inheritance: - Multiple genes + environmental factors - No clear Mendelian pattern - Examples: Diabetes, hypertension, coronary artery disease, cleft lip/palate 3. Chromosomal disorders: - Abnormalities in chromosome number or structure - Examples: Down syndrome (trisomy 21), Turner syndrome (45,X), Klinefelter syndrome (47,XXY) Other important categories: - Trinucleotide repeat disorders - Mitochondrial DNA disorders - Disorders with genomic imprinting --- SECTION C: MENDELIAN DISORDERS - GENERAL CONCEPTS (5 Questions) 12. Define Mendelian disorders and key genetic concepts. Answer: Mendelian disorders: - Fall under mutations in single genes of large effect - Follow Mendel's laws of inheritance - Clear inheritance patterns Key statistics: - Every person carries 5-8 deleterious genes - Most are recessive - 80% familial (inherited) - 20% de novo (new mutations) Important concepts: Gene expression: - Dominant, recessive, or co-dominant Pleiotropy: - Single mutant gene → multiple end effects - Example: Marfan syndrome affects eyes, skeleton, cardiovascular system Genetic heterogeneity: - Mutations at different loci → same trait/disease