Genetic Disorders CAT: Key Terms & OmpathStudy

MBPA 3413 Genetic Disorders CAT 2 (short answer format) . --- SECTION A: Short Answer Questions Q1. Define the following terms: (5 marks) a. Pleiotropism — The phenomenon whereby a single mutant gene produces multiple, seemingly unrelated phenotypic effects (e.g., sickle cell mutation causing anaemia, painful crises, splenic infarction, and susceptibility to infection all from one gene defect). b. Penetrance — The proportion of individuals carrying a particular genotype who actually express the associated phenotype. Expressed as a percentage (e.g., 80% penetrance means 80% of carriers show the trait; if less than 100%, it's called "incomplete/reduced penetrance"). c. Variability (variable expressivity) — The degree to which a phenotype is expressed can differ between individuals carrying the same genotype/mutation — i.e., the severity or specific features of a disorder vary from person to person even with the same underlying mutation. d. Polymorphisms — Genetic variants that occur commonly in the population (present in ≥1% of individuals), generally without significant harmful consequence, representing normal human genetic diversity (e.g., blood groups, SNPs). e. Mutation — A permanent, heritable alteration in the DNA nucleotide sequence, which may be inherited (germline) or acquired during a person's lifetime (somatic). --- Q2. Compare and contrast autosomal dominant and autosomal recessive disorders. (10 marks) Feature Autosomal Dominant Autosomal Recessive --- --- --- Gene copies required to express disease Only one mutant allele (heterozygous state) Both alleles must be mutant (homozygous state); heterozygotes are carriers Inheritance pattern Vertical transmission — disease typically appears in every generation Often skips generations — appears in siblings of a generation, not necessarily parents Parents of affected child Usually one parent is affected Usually both parents are unaffected carriers Sex distribution Males and females equally affected and equally able to transmit Males and females equally affected Recurrence risk 50% risk to each child of an affected parent 25% risk to each child of two carrier parents Age of onset Often later onset (adulthood) Often earlier onset (childhood/infancy) Severity/nature of defect Frequently involves defects in structural proteins or receptors; often shows variable expressivity and reduced penetrance Frequently involves defects in enzymes (loss-of-function); tends to be more uniform/severe in expression, complete penetrance more common Consanguinity Not a significant risk factor Increased risk with consanguineous unions (both parents more likely to carry the same rare recessive allele) New mutations Can occur as new (de novo) mutations, presenting in a child of unaffected parents New mutations are less commonly the presenting mechanism; typically inherited from two carrier parents Examples Huntington disease, Marfan syndrome, familial hypercholesterolemia, achondroplasia, polycystic kidney disease Cystic fibrosis, phenylketonuria, sickle cell anaemia, Tay-Sachs disease, galactosemia --- SECTION B: Long Answer Question Q1. Describe the various types of cytogenetic abnormalities associated with disease in human beings. (17 marks) Cytogenetic (chromosomal) abnormalities are broadly divided into numerical and structural abnormalities, and may affect either autosomes or sex chromosomes . 1. Numerical abnormalities Aneuploidy — Any chromosome number that is not an exact multiple of the haploid number (n), usually resulting from nondisjunction during meiosis (or occasionally mitosis). Trisomy (2n+1) — an extra copy of one chromosome. Examples: Trisomy 21 (Down syndrome), Trisomy 18 (Edwards syndrome), Trisomy 13 (Patau syndrome). Monosomy (2n−1) — loss of one chromosome copy. Example: 45,X (Turner syndrome). Autosomal monosomies are generally lethal in utero. Sex chromosome aneuploidies — e.g., 47,XXY (Klinefelter syndrome), 47,XYY, 47,XXX; generally better tolerated than autosomal aneuploidies due to X-inactivation (lyonization). Polyploidy — Exact multiples of the haploid number greater than diploid (e.g., triploidy 3n, tetraploidy 4n); usually incompatible with life and a common cause of spontaneous miscarriage. 2. Structural abnormalities — arise from chromosome breakage followed by abnormal reunion: Translocations Reciprocal translocation — exchange of segments between two non-homologous chromosomes (e.g., t(9;22) BCR-ABL in chronic myeloid leukemia). Robertsonian translocation — fusion of two acrocentric chromosomes at the centromere with loss of short arms (e.g., 14;21 translocation causing familial Down syndrome). Deletions — loss of a chromosomal segment. Examples: Cri du chat syndrome (deletion of short arm of chromosome 5, 5p−), 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome). Duplications — extra copy of a chromosomal segment, leading to partial trisomy for that region. Inversions — a segment of a chromosome breaks and reinserts in reverse or