Genetic Disorders

Why This Matters

Genetic disorders represent the direct consequences of mutations, chromosomal abnormalities, and inheritance patterns—core concepts you'll be tested on throughout your genetics course. 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. These disorders serve as real-world case studies 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. Each disorder illustrates a principle that 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. When homologous chromosomes or sister chromatids fail to separate properly, gametes receive too many or too few chromosomes.

Down Syndrome

• Trisomy 21—caused by three copies of chromosome 21, usually resulting from maternal nondisjunction during meiosis I
• Phenotypic features include developmental delays, characteristic facial features, and increased risk of congenital heart defects
• Associated conditions include early-onset Alzheimer's disease and increased leukemia risk, demonstrating gene dosage effects

Klinefelter Syndrome

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

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Autosomal Recessive Disorders

These conditions require two mutant alleles for disease expression. Carriers (heterozygotes) are typically unaffected, and affected individuals often have unaffected parents. Most involve loss-of-function mutations in enzyme-coding genes.

Cystic Fibrosis

• CFTR gene mutation—most commonly the $\Delta F508$ deletion, which causes misfolding of the chloride channel protein
• Pathophysiology involves defective chloride transport, leading to thick, dehydrated mucus in lungs and pancreas
• Heterozygote advantage—carriers may have increased resistance to cholera and typhoid, explaining the mutation's persistence in populations

Sickle Cell Anemia

• HBB gene point mutation—a single nucleotide change ($GAG \rightarrow GTG$) substitutes valine for glutamic acid in beta-globin
• Hemoglobin S polymerizes under low oxygen, causing red blood cells to adopt a rigid, sickle shape that blocks capillaries
• Heterozygote advantage—carriers (sickle cell trait) have increased resistance to Plasmodium falciparum malaria

Tay-Sachs Disease

• Hexosaminidase A deficiency—mutations prevent breakdown of GM2 gangliosides, which accumulate in neurons
• Progressive neurodegeneration begins in infancy with developmental regression, seizures, and loss of motor function
• Population genetics—elevated carrier frequency in Ashkenazi Jewish populations due to founder effect and possible heterozygote advantage

Phenylketonuria (PKU)

• Phenylalanine hydroxylase deficiency—inability to convert phenylalanine to tyrosine causes toxic accumulation
• Neurological damage results from phenylalanine buildup if untreated, leading to intellectual disability
• Newborn screening success—early detection and dietary restriction of phenylalanine prevents symptoms entirely

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X-Linked Recessive Disorders

These conditions primarily affect males because they have only one X chromosome (hemizygous). Females are typically carriers, and affected males inherit the mutant allele from their carrier mothers. Look for the characteristic pedigree pattern: no male-to-male transmission.

Duchenne Muscular Dystrophy

• Dystrophin gene mutations—large deletions or frameshift mutations eliminate functional dystrophin protein in muscle cells
• Progressive muscle degeneration begins in early childhood, with most patients wheelchair-dependent by adolescence
• Becker muscular dystrophy—caused by in-frame mutations that produce partially functional dystrophin, resulting in milder symptoms

Hemophilia

• Clotting factor deficiencies—Hemophilia A (factor VIII) and Hemophilia B (factor IX) both cause prolonged bleeding
• Spontaneous bleeding episodes occur in joints and muscles; severity correlates with residual clotting factor activity
• Royal disease—historically traced through European royal families, demonstrating X-linked inheritance across generations

Fragile X Syndrome

• FMR1 gene CGG repeat expansion—normal alleles have 5-44 repeats; full mutations exceed 200 repeats and silence the gene
• FMRP protein loss disrupts synaptic development, causing intellectual disability and behavioral challenges
• Anticipation—repeat length tends to increase across generations, explaining why premutation carriers can have affected children

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Trinucleotide Repeat Disorders

These conditions involve unstable DNA sequences where short nucleotide repeats expand beyond a threshold, disrupting gene function. Repeat length often correlates with severity, and expansions can increase across generations (anticipation).

Huntington's Disease

• CAG repeat expansion in the HTT gene—normal alleles have fewer than 36 repeats; disease alleles have 40 or more
• Autosomal dominant with complete penetrance—only one mutant allele is needed, and all carriers eventually develop symptoms
• Gain-of-function mechanism—the expanded polyglutamine tract causes protein aggregation and neuronal death in the basal ganglia

Fragile X Syndrome

• CGG repeat expansion in the FMR1 gene promoter region silences transcription through DNA methylation
• Loss-of-function mechanism—unlike Huntington's, the expanded repeat prevents protein production rather than creating a toxic product
• Sherman paradox—risk increases in successive generations as premutation alleles expand to full mutations

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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?