Genetic Disorders Pathology Crash Course: OmpathStudy

--- MBPA 3413 & MBPA 3412 — Exam Crash Course Notes General Pathology II & III Point-form, comprehensive Section One: Genetic Disorders (MBPA 3413) Mutations, Mendelian Disorders, Molecular Diagnosis, Chromosomal Disorders, Complex Multigenic Disorders 1.1 Key Definitions Genetics — study of individual genes and heredity Genomics — study of the entire genome (all genes + interactions) Genetic disorder — disease caused by abnormality in an individual's DNA DNA (Deoxyribonucleic acid) — double-stranded molecule carrying genetic instructions Exons — coding sequences of DNA that are expressed into protein Introns — non-coding sequences within a gene; spliced out before translation Intergenic regions — DNA between genes; mostly non-coding SNP (Single Nucleotide Polymorphism) — variation at a single base pair; occurs ~every 1,000 bp; used as genetic markers Epigenetics — heritable changes in gene expression without altering DNA sequence Proteomics — large-scale study of all proteins expressed by a genome Bioinformatics — use of computational tools to analyse biological data (e.g., genome sequences) Genotype — the genetic makeup of an individual Phenotype — observable characteristics resulting from genotype + environment Gene therapy — treatment of disease by correcting/replacing defective genes Hereditary — passed from parent to child through the germline Familial — runs in families but not necessarily purely genetic Congenital — present at birth (may or may not be genetic) Mutation — permanent change in DNA sequence DNA microarray analysis — "gene chip" technology; interrogates thousands of genes simultaneously on a single platform Recombinant DNA technology — lab technique of joining DNA from different sources to produce new genetic combinations 1.2 Mutations Definition: permanent change in the DNA; can be inherited (germline) or acquired (somatic) Categories of mutations Genome mutations — loss/gain of whole chromosomes → monosomies / trisomies Chromosome mutations — visible structural rearrangements of chromosomes Gene mutations — partial/complete deletion of a gene or single base pair change Types of gene mutations Point mutations (substitutions) Missense — changes one amino acid to another (conservative or non-conservative, e.g. sickle cell anaemia) Nonsense — changes an amino acid codon to a stop codon → truncated, non-functional protein Frameshift mutations — insertion/deletion of 1 or 2 base pairs → shifts the entire reading frame → abnormal protein Deletions / insertions < 3 base pairs → frameshift Multiples of 3 → missing amino acid(s) but frame intact → abnormal protein Trinucleotide repeat mutations — dynamic amplification of a 3-nucleotide sequence (e.g. Huntington's disease) Promoter/enhancer mutations — disrupt transcription factor binding → reduced or absent gene expression (e.g. some hereditary haemolytic anaemias) How mutations cause genetic disease — through: Enzyme defects → failure of metabolic pathways Enzyme inhibitor defects Defective receptors → impaired cell signalling Defective transport systems Abnormal structural proteins (e.g. collagen disorders) Defects in haemostasis Defects in growth regulation Adverse drug reactions (pharmacogenomics) 1.3 Mendelian Disorders & Transmission Patterns Key facts Every person carries 5–8 deleterious genes (mostly recessive) 80% of mutations are familial; the remainder are de novo Pleiotropism — one mutant gene produces many effects Genetic heterogeneity — mutations at different loci produce the same phenotype Autosomal Dominant (AD) At least one parent usually affected (de novo possible in older fathers) Affects males and females equally Both sexes can transmit the disorder 50% risk per pregnancy Features: reduced penetrance, variable expressivity, often delayed onset Mechanisms: reduced gene product production, or production of an inactive/abnormal protein Autosomal Recessive (AR) Largest category of Mendelian disorders Parents usually unaffected (carriers); siblings may be affected 25% recurrence risk per birth More uniform expression than AD; complete penetrance common Onset frequently early in life Includes nearly all inborn errors of metabolism Consanguinity increases risk X-Linked Disorders Almost all X-linked disorders are recessive Affected males do not transmit to sons — daughters become carriers Carrier females may show mild features X-linked dominant is rare (e.g. vitamin D-resistant rickets) 1.4 Molecular Diagnosis of Mendelian & Complex Disorders Background Field emerged in the latter 20th century via karyotyping and Southern blotting Four advances drove expansion: ① human genome sequencing ② PCR kits ③ microarrays ④ next-generation sequencing Mutations tested can be germline (in every cell, e.g. CFTR in cystic fibrosis) or somatic (tissue-specific, e.g. NMYC in neuroblastoma) Diagnosis of copy number abnormalities Method What it detects --- --- G-banding karyotype Whole chromosome changes; low resolution FISH Specific chromosomal region