Clinical Genetics: Master Mendelian OmpathStudy

GENETIC DISORDERS: A FOUNDATIONAL GUIDE Mount Kenya University — School of Medicine Human Pathology / Medical Genetics — Year 3 MBChB --- Why Genetics Is Clinically Important The scale of the problem Approximately 5% of individuals under 25 years develop a serious disease with a significant genetic component — this is not a rare, footnote topic Genetic diagnosis and screening are generally neither easy nor cheap Only around 50% of early pregnancy miscarriages show demonstrable chromosomal abnormalities — not 100%, a common exam trap The three master categories Every genetic disorder falls into one of three buckets. Identify the bucket first, and the rest of the logic follows: 1. Mendelian (single-gene) disorders — one gene, one major effect, predictable inheritance pattern 2. Chromosomal disorders — whole chromosomes or large segments missing, extra, or rearranged 3. Complex/multigenic disorders — many genes interacting with environment (e.g., diabetes, hypertension, most common adult diseases) --- Mendelian Inheritance — The Underlying Logic Understand why each pattern behaves the way it does — the disease lists become obvious afterward. Autosomal Dominant (AD) One abnormal copy of the gene (from either parent) is sufficient to cause disease, because the gene sits on a non-sex chromosome Pattern on a family tree: disease appears in every generation, no skipping; affected parent has 50% chance of passing it to each child; both sexes equally affected Molecular theme: typically involves structural proteins (collagen, cytoskeletal proteins) or receptors — one bad copy disrupts structure even with a normal copy present Onset: often adulthood Disorders to know as a set: Marfan syndrome (fibrillin-1), Huntington disease (trinucleotide repeat), familial hypercholesterolemia (LDL receptor defect), polycystic kidney disease, hereditary spherocytosis (~75% of cases) Autosomal Recessive (AR) Need TWO abnormal copies (one from each parent) to manifest disease; single copy = silent carrier Pattern: skips generations; both sexes equally affected; parents typically unaffected carriers; often only one sibling affected Molecular theme: typically involves enzyme deficiencies — one working copy usually produces enough enzyme to avoid disease Onset: often childhood Disorders to know as a set: phenylketonuria, galactosemia, glycogen storage diseases, mucopolysaccharidoses, sickle cell anaemia (structural protein exception — one normal beta-globin gene still makes enough normal haemoglobin), most lysosomal storage diseases X-linked Recessive Gene is on the X chromosome. Males have only one X, so a single abnormal copy causes disease. Females have two X's, so need two abnormal copies to be affected — usually just carriers Pattern: almost exclusively affects males; affected males cannot pass it to sons; carrier mothers pass it to 50% of sons (affected) and 50% of daughters (carriers) Key example: Duchenne muscular dystrophy (DMD) — the most tested X-linked recessive disorder in this course Why carrier females are usually protected: random X-inactivation (lyonization) means roughly half their cells express the normal X The trap option "All sex-linked disorders are X-linked recessive" is FALSE: Y-linked disorders exist (rare), and X-linked dominant disorders exist too (e.g., vitamin D–resistant rickets). --- The Molecular Basis — Mutations Types of mutation Missense: one amino acid swapped for another; protein still made but altered. Sickle cell anaemia is the textbook example — Glu→Val substitution at codon 6 of beta-globin Nonsense: a codon becomes a "stop" signal, truncating the protein — usually far more damaging than missense Silent: DNA changes, but the resulting amino acid is the same (codon redundancy) — no effect on protein SNPs (Single Nucleotide Polymorphisms) The most common form of human genetic variation Almost always biallelic Millions exist across the genome (not "less than 100") Majority lie outside coding regions (not "99% in coding regions") Used clinically for disease-risk stratification CNVs (Copy Number Variations) Large contiguous stretches of DNA that vary in copy number between individuals Responsible for millions of base pairs of difference between any two people DO involve coding sequences/genes — a common false-statement trap says otherwise Immune system and nervous system genes disproportionately affected Can be biallelic or complex (multiple alleles) Epigenetics Modulation of gene or protein expression without any change to the underlying DNA sequence — via DNA methylation, histone modification Not the same as a silent mutation (that's DNA-sequence-level) Becomes critical later in genomic imprinting (Prader-Willi, Angelman) --- Lysosomal Storage Diseases — A High-Yield Cluster Disease Enzyme deficiency Substance accumulated --- --- --- Tay-Sachs disease Hexosaminidase A GM2 ganglioside Niemann-Pick A/B Sphingomyelinase Sphingomyelin Niemann-Pick C Defect in intracellular cholesterol transport Cholestero