Genetic Disorders

Why This Matters

Genetic disorders are the direct consequences of mutations, chromosomal abnormalities, and inheritance patterns. Understanding these conditions isn't just about memorizing symptoms; it's about recognizing how different types of genetic changes (point mutations, trinucleotide repeats, chromosomal nondisjunction, X-linked inheritance) manifest in human phenotypes. Each disorder is a case study for concepts like autosomal dominant vs. recessive inheritance, loss-of-function mutations, and dosage effects.

When you encounter these disorders on exams, you're being tested on your ability to connect genotype to phenotype, predict inheritance patterns, and explain molecular mechanisms. Don't just memorize that cystic fibrosis affects the lungs; know why a chloride channel mutation leads to thick mucus. Don't just recall that Huntington's is dominant; understand how a trinucleotide repeat expansion causes neurodegeneration. Any of these disorders could appear in multiple-choice questions, pedigree analysis, or FRQ prompts.

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Chromosomal Abnormalities

These disorders result from errors in chromosome number or structure, typically arising from nondisjunction during meiosis. Nondisjunction is the failure of homologous chromosomes (in meiosis I) or sister chromatids (in meiosis II) to separate properly, producing gametes with too many or too few chromosomes.

Down Syndrome

• Trisomy 21: three copies of chromosome 21, most often resulting from maternal nondisjunction during meiosis I. The risk increases with maternal age because oocytes remain arrested in meiosis I for decades, increasing the chance of segregation errors.
• Phenotypic features include developmental delays, characteristic facial features, and increased risk of congenital heart defects.
• Gene dosage effects are central here: having 1.5× the normal dose of chromosome 21 genes drives the phenotype. Associated conditions include early-onset Alzheimer's disease (the APP gene sits on chromosome 21) and increased leukemia risk.

Klinefelter Syndrome

• 47,XXY karyotype: males inherit an extra X chromosome from nondisjunction in either parent.
• Hormonal effects include reduced testosterone production, infertility, gynecomastia, and often taller stature.
• X-inactivation partially compensates for the extra X, which is why symptoms are relatively mild compared to autosomal trisomies.

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Autosomal Recessive Disorders

These conditions require two mutant alleles (homozygous) for disease expression. Carriers (heterozygotes) are typically unaffected, and affected individuals often have unaffected parents who are both carriers. Most involve loss-of-function mutations in enzyme-coding genes, which makes sense: one functional copy of an enzyme gene usually produces enough protein to maintain normal metabolism.

Cystic Fibrosis

• CFTR gene mutation: most commonly the $\Delta F508$ deletion (a 3-bp deletion removing a phenylalanine at position 508), which causes misfolding of the CFTR chloride channel protein. The misfolded protein gets degraded before reaching the cell membrane.
• Pathophysiology: without functional CFTR, chloride ions can't move out of epithelial cells. Water follows chloride by osmosis, so secretions in the lungs and pancreas become thick and dehydrated. This sticky mucus traps bacteria and blocks pancreatic ducts.
• Heterozygote advantage: carriers may have increased resistance to cholera and typhoid fever, which helps explain why this mutation persists at relatively high frequency in European-descended populations.

Sickle Cell Anemia

• HBB gene point mutation: a single nucleotide change ($GAG \rightarrow GTG$) substitutes valine for glutamic acid at position 6 in beta-globin. This is a classic missense mutation.
• Hemoglobin S polymerizes under low-oxygen conditions because the hydrophobic valine residue creates sticky patches on the protein surface. The polymerized hemoglobin distorts red blood cells into a rigid sickle shape that blocks capillaries, causing pain crises and organ damage.
• Heterozygote advantage: carriers (sickle cell trait, genotype $HbA/HbS$) have increased resistance to Plasmodium falciparum malaria. This is the textbook example of balancing selection, and it explains why the $HbS$ allele is most common in malaria-endemic regions.

Tay-Sachs Disease

• Hexosaminidase A deficiency: mutations in the HEXA gene prevent breakdown of GM2 gangliosides, which accumulate in lysosomes of neurons. This is a lysosomal storage disorder.
• Progressive neurodegeneration begins in infancy (around 3-6 months) with developmental regression, seizures, and loss of motor function. The disease is fatal, typically by age 3-5.
• Population genetics: elevated carrier frequency (~1 in 30) in Ashkenazi Jewish populations, likely due to founder effect and genetic drift, with possible heterozygote advantage.

Phenylketonuria (PKU)

• Phenylalanine hydroxylase (PAH) deficiency: the enzyme that converts phenylalanine to tyrosine is nonfunctional, causing toxic accumulation of phenylalanine in the blood and brain.
• Neurological damage from phenylalanine buildup leads to intellectual disability if untreated. Tyrosine also becomes an essential amino acid in PKU patients since they can't synthesize it.
• Newborn screening success: PKU is detected through routine heel-prick blood tests. Early dietary restriction of phenylalanine prevents symptoms entirely, making this a key example of how environment can modify genetic phenotype.

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X-Linked Recessive Disorders

These conditions primarily affect males because they have only one X chromosome (hemizygous). A single mutant allele on the X is enough to cause disease in males, while females need two copies. Females are typically carriers, and affected males inherit the mutant allele from their carrier mothers. The hallmark pedigree pattern: no male-to-male transmission, because fathers pass their Y chromosome (not X) to sons.

Duchenne Muscular Dystrophy

• Dystrophin gene mutations: large deletions or frameshift mutations eliminate functional dystrophin protein. The DMD gene is one of the largest in the human genome (~2.4 Mb), which partly explains its high mutation rate.
• Progressive muscle degeneration begins in early childhood (ages 2-5), with most patients wheelchair-dependent by adolescence. Without dystrophin linking the cytoskeleton to the extracellular matrix, muscle fibers tear during contraction and are gradually replaced by fibrotic tissue.
• Becker muscular dystrophy is caused by in-frame deletions or mutations that produce a partially functional (but shorter) dystrophin protein, resulting in milder, later-onset symptoms. This Duchenne vs. Becker comparison nicely illustrates the difference between frameshift (severe) and in-frame (milder) mutations in the same gene.

Hemophilia

• Clotting factor deficiencies: Hemophilia A (factor VIII deficiency, ~80% of cases) and Hemophilia B (factor IX deficiency) both cause prolonged bleeding due to impaired coagulation cascade function.
• Spontaneous bleeding episodes occur in joints and muscles; severity correlates with residual clotting factor activity (severe < 1%, moderate 1-5%, mild 5-40%).
• Historical significance: traced through European royal families descended from Queen Victoria, providing a well-documented pedigree demonstrating X-linked inheritance across generations.

Fragile X Syndrome

• FMR1 gene CGG repeat expansion: normal alleles have 5-44 repeats; premutation alleles have 55-200 repeats; full mutations exceed 200 repeats and trigger methylation that silences the gene.
• FMRP protein loss disrupts synaptic plasticity and dendritic spine development, causing intellectual disability (the most common inherited cause), behavioral challenges, and characteristic physical features like a long face and large ears.
• Anticipation: repeat length tends to increase across generations, especially during maternal transmission. This explains why a grandmother with a premutation can have a grandson with a full mutation and severe symptoms.

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Trinucleotide Repeat Disorders

These conditions involve unstable DNA sequences where short nucleotide repeats expand beyond a critical threshold, disrupting gene function. Two key features define this category: repeat length correlates with disease severity, and expansions tend to increase across generations, a phenomenon called anticipation.

Huntington's Disease

• CAG repeat expansion in the HTT gene: normal alleles have fewer than 36 repeats; disease alleles have 40 or more. Alleles with 36-39 repeats show reduced penetrance.
• Autosomal dominant with essentially complete penetrance above 40 repeats. Only one mutant allele is needed, and all carriers eventually develop symptoms, typically between ages 30-50.
• Gain-of-function mechanism: the expanded CAG repeat encodes an abnormally long polyglutamine tract. This causes the huntingtin protein to misfold, aggregate, and form toxic inclusions that kill neurons, particularly in the striatum of the basal ganglia. The normal huntingtin protein still functions; the problem is the toxic new property of the mutant protein.

Fragile X Syndrome

• CGG repeat expansion in the FMR1 gene promoter region silences transcription through DNA methylation. Once the repeat exceeds ~200 copies, CpG methylation spreads across the promoter and shuts the gene down.
• Loss-of-function mechanism: unlike Huntington's, the expanded repeat doesn't create a toxic product. Instead, it prevents FMRP from being made at all. The disease results from absence of a necessary protein.
• Sherman paradox: the observation that disease risk increases in successive generations. This puzzled geneticists before the molecular basis of trinucleotide repeat expansion was understood. Premutation alleles (55-200 repeats) are unstable during meiosis and can expand to full mutations in offspring.

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Quick Reference Table

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Self-Check Questions

1. Which two disorders demonstrate heterozygote advantage, and what selective pressure maintains each mutation in the population?

2. Compare the molecular mechanisms of Huntington's disease and Fragile X syndrome. How does the same type of mutation (trinucleotide repeat expansion) cause disease through different pathways?

3. A pedigree shows affected males in every generation, but no affected females and no father-to-son transmission. Which inheritance pattern does this suggest, and which disorders from this guide fit this pattern?

4. Both Tay-Sachs disease and PKU are autosomal recessive enzyme deficiencies that cause neurological damage. Why can PKU be effectively treated while Tay-Sachs cannot?

5. If an FRQ asks you to explain how nondisjunction leads to different phenotypic outcomes depending on which chromosome is affected, which two disorders would you compare and what key difference would you emphasize?