# Lecture 13: Molecular Genetics and Mutations ## Unit 1.1: Foundations of Medicine & Medical Sciences --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Classify types of mutations based on their molecular nature and effects on protein function 2. Explain Mendelian inheritance patterns including autosomal dominant, autosomal recessive, and X-linked 3. Describe non-Mendelian inheritance patterns including mitochondrial, imprinting, and trinucleotide repeats 4. Explain the principles of genetic testing and the types of tests available 5. Identify common genetic disorders and their inheritance patterns 6. Apply genetic principles to calculate inheritance risks in families --- ## Introduction to Medical Genetics ### Basic Terminology Understanding medical genetics requires mastery of fundamental terminology. A gene is a segment of DNA that encodes a functional product, typically a protein but sometimes a functional RNA. An allele is an alternative form of a gene—different versions that can exist at the same chromosomal location (locus). Because humans have two copies of each autosomal chromosome, we carry two alleles for each gene located on autosomes. The genotype refers to the specific alleles an individual possesses, while the phenotype describes the observable characteristics that result from that genotype in interaction with the environment. A key insight of genetics is that the relationship between genotype and phenotype is often complex: the same genotype may produce different phenotypes depending on other genes, environmental factors, and chance. ### Homozygosity and Heterozygosity When an individual carries two identical alleles at a locus, they are homozygous for that allele (AA or aa). When the two alleles differ, the individual is heterozygous (Aa). For genes on the X chromosome, males are hemizygous—they have only one copy of each X-linked gene because they have only one X chromosome. This hemizygosity explains why X-linked recessive conditions primarily affect males: they lack a second copy of the gene that could compensate for a mutant allele. Panel A: Homozygous dominant showing a pair of homologous X-shaped chromosomes both carrying the "A" allele (blue) at the indicated locus, with genotype AA and phenotype "A expressed." Panel B: Heterozygous showing one chromosome with "A" (blue) and one with "a" (red), with genotype Aa and phenotype described as "Carrier." Panel C: Homozygous recessive showing both chromosomes carrying the "a" allele (red), with genotype aa and phenotype showing recessive trait expressed. Panel D: A single X chromosome in a male illustrating hemizygosity for X-linked genes, with only one allele present and no second copy for compensation. --- ## Types of Mutations ### Classification by Size Mutations range from single nucleotide changes to alterations involving entire chromosomes. Understanding this spectrum is essential for selecting appropriate genetic tests and interpreting their results. Point mutations involve changes to a single nucleotide. When one purine replaces another (A↔G) or one pyrimidine replaces another (C↔T), this is called a transition; these are more common because they preserve the ring structure. When a purine replaces a pyrimidine or vice versa, this is a transversion. Small insertions and deletions (indels) involve 1-50 base pairs. If the number of bases inserted or deleted is not a multiple of three, the mutation disrupts the reading frame—a frameshift mutation that alters all codons downstream and typically produces a nonfunctional protein. Large-scale mutations affect segments of chromosomes. Deletions remove genetic material; duplications create extra copies. Inversions flip a segment into the opposite orientation, and translocations move segments between non-homologous chromosomes. These can be balanced (no net gain or loss of genetic material) or unbalanced (with deletions or duplications). Balanced rearrangements may not affect the carrier but can produce unbalanced offspring. ### Classification by Effect on Protein Silent (synonymous) mutations change a codon without changing the encoded amino acid. Due to the degeneracy of the genetic code, particularly at the third (wobble) position, many nucleotide changes do not alter the protein sequence. Silent mutations are usually clinically benign, though rare exceptions can affect mRNA splicing, stability, or translation efficiency. Missense mutations change one amino acid to another. Their clinical impact varies enormously depending on the specific substitution. Replacing one amino acid with another of similar properties (a conservative substitution) may have minimal effect, while replacing a small, hydrophobic amino acid with a large, charged one at a critical site may be devastating. The classic example is sickle cell disease: a single glutamate-to-valine substitution at position 6 of β-globin (HbS, or Glu6Val) causes hemoglobin to polymerize under low oxygen conditions. Nonsense mutations create a premature stop codon, typically producing a truncated, nonfunctional protein. Moreover, mRNAs containing premature stop codons are often degraded by the nonsense-mediated decay (NMD) surveillance pathway, preventing even truncated protein from being made. Nonsense mutations usually cause loss of function. Frameshift mutations result from insertions or deletions that are not multiples of three nucleotides. They shift the reading frame so that all codons downstream are misread, typically producing a completely different amino acid sequence until a stop codon is encountered in the new frame. Frameshifts almost always abolish protein function. Panel A: Silent mutation showing a single nucleotide change (CGA to CGG) that still encodes arginine with no protein change (green checkmark), compared to the reference DNA/mRNA/protein sequence, with clinical consequence noted as usually benign. Panel B: Missense mutation showing a change (GAG to GUG) converting Glu to Val, illustrated with the sickle cell mutation in beta-globin, with clinical consequence noted as variable effect. Panel C: Nonsense mutation showing a change (CGA to UGA) creating a premature stop codon, with the protein terminating early as a truncated fragment (red X) and NMD degradation noted, with clinical consequence of loss of function. Panel D: Frameshift mutation showing deletion of one nucleotide shifting the reading frame so all downstream amino acids are altered (shown in different colors), often leading to a premature stop, with clinical consequence of usually loss of function. ### Splice Site Mutations Mutations affecting splice sites deserve special attention because they account for 15-50% of disease-causing mutations—making splicing defects the most common mechanism by which point mutations cause disease. Mutations can destroy canonical splice sites (the invariant GU at the 5' splice site or AG at the 3' splice site), leading to exon skipping or intron retention. Mutations can also create new splice sites within introns or exons (cryptic splice sites), or alter splicing regulatory sequences, changing the ratio of alternatively spliced isoforms. The consequences are often severe because the resulting mRNA encodes an abnormal protein. --- ## Consequences of Mutations ### Loss of Function Loss-of-function mutations reduce or eliminate normal protein activity. Most loss-of-function mutations are recessive at the phenotypic level: as long as one functional allele remains, it produces enough protein for normal function. Only when both alleles are mutated (homozygous or compound heterozygous) does disease result. Cystic fibrosis exemplifies this pattern—carriers with one mutant CFTR allele are unaffected, but individuals with two mutant alleles develop the disease. ### Gain of Function Gain-of-function mutations produce new or enhanced activity. Because only one mutant allele is needed to create the abnormal activity, these mutations are typically dominant. Achondroplasia results from a gain-of-function mutation in FGFR3 that causes the receptor to be constitutively active, inhibiting bone growth even in the absence of ligand. Many oncogenic mutations are gain-of-function, producing hyperactive growth signals. ### Dominant Negative Dominant negative mutations produce a protein that interferes with the function of the normal protein. This is particularly common when proteins function as multimers. In osteogenesis imperfecta, mutations in collagen genes can produce abnormal chains that are incorporated into collagen fibrils, disrupting the entire structure even though normal chains are also present. The mutant protein "poisons" the complex, making the effect worse than simply losing one copy of the gene. ### Haploinsufficiency Some genes require both copies to produce enough protein for normal function—one copy is insufficient. Mutations in such genes are dominant because heterozygotes are affected. Familial hypercholesterolemia illustrates this: individuals with one mutant LDL receptor allele have elevated cholesterol because half the normal receptor number cannot clear LDL adequately. Williams syndrome results from haploinsufficiency of elastin and neighboring genes following microdeletion of chromosome 7q11.23. --- ## Mendelian Inheritance Patterns ### Autosomal Dominant Autosomal dominant conditions affect both males and females equally and typically appear in every generation of an affected family—a vertical pattern of transmission. An affected individual has a 50% chance of passing the mutant allele to each offspring. Unaffected individuals do not carry the mutation and cannot transmit it. Important concepts modify this simple picture. Variable expressivity means that affected individuals may show different severity—some family members with Marfan syndrome may have severe aortic disease while others have only subtle skeletal features. Incomplete penetrance means not everyone carrying the mutation expresses the phenotype—some BRCA1 carriers never develop cancer. New mutations (de novo mutations) explain cases appearing without family history—about 80% of achondroplasia cases result from new mutations, with unaffected parents. Classic autosomal dominant disorders include Huntington disease (progressive neurodegeneration), Marfan syndrome (connective tissue disorder with aortic and skeletal involvement), neurofibromatosis type 1 (cafe-au-lait spots, neurofibromas), and familial hypercholesterolemia (early coronary disease). Panel A: Three-generation pedigree showing affected individuals (filled symbols) appearing in every generation, equally distributed between males (squares) and females (circles), with vertical transmission from parent to child. Panel B: Unaffected individuals (open symbols) showing that no generation is skipped and the trait follows a vertical pattern of inheritance. Panel C: Punnett square with an affected heterozygote (Aa) crossed with an unaffected homozygote (aa) producing 50% Aa (affected) and 50% aa (unaffected) offspring. Panel D: Key features annotated: "vertical transmission," "both sexes equally affected," "50% risk to offspring of affected parent," with examples of autosomal dominant disorders listed. ### Autosomal Recessive Autosomal recessive conditions also affect both sexes equally but typically show a horizontal pattern—affected individuals are siblings, with unaffected parents who are obligate carriers. When two carriers have children, each pregnancy has a 25% chance of producing an affected child (homozygous mutant), 50% chance of a carrier (heterozygote), and 25% chance of an unaffected non-carrier (homozygous normal). Consanguinity (parents related by blood) increases the risk of autosomal recessive conditions because related individuals are more likely to carry the same rare mutation inherited from a common ancestor. Carrier frequencies for common recessive diseases vary by population: cystic fibrosis affects approximately 1 in 2,500 Caucasians (carrier frequency ~1 in 25), while sickle cell disease affects approximately 1 in 500 African Americans (carrier frequency ~1 in 12—elevated because the carrier state confers malaria resistance). Examples include cystic fibrosis (chronic lung disease, pancreatic insufficiency), phenylketonuria (intellectual disability prevented by dietary restriction), Tay-Sachs disease (fatal neurodegeneration), and sickle cell disease (hemolytic anemia, vaso-occlusion). Panel A: Pedigree showing two unaffected carrier parents (half-filled symbols) with affected children (fully filled symbols), demonstrating horizontal transmission within a sibship. Panel B: Grandparents typically unaffected and the affected individuals' children shown as obligate carriers (half-filled symbols), illustrating the inheritance pattern across generations. Panel C: Punnett square showing Aa x Aa producing 1/4 AA (unaffected non-carrier), 1/2 Aa (unaffected carrier, half-filled), and 1/4 aa (affected), with ratios 25%-50%-25% clearly labeled. Panel D: Key features annotated: "horizontal pattern," "carrier parents," "consanguinity increases risk," with note on carrier frequency calculations. ### X-Linked Recessive X-linked recessive conditions predominantly affect males because they have only one X chromosome—any mutant allele on that X will be expressed without compensation from a second X. Females with one mutant allele are typically unaffected carriers, though they may show mild manifestations due to variable X-inactivation patterns. A key feature distinguishing X-linked from autosomal inheritance is the absence of male-to-male transmission: affected fathers pass their X chromosome to daughters (who become carriers), not to sons (who receive the father's Y chromosome). All daughters of affected males are obligate carriers. A carrier mother has a 50% chance of transmitting the mutant allele to each child—sons who inherit it are affected; daughters who inherit it are carriers. Duchenne muscular dystrophy (progressive muscle weakness leading to death in early adulthood), hemophilia A and B (deficient blood clotting), G6PD deficiency (hemolytic anemia triggered by oxidant stress), and red-green color blindness exemplify X-linked recessive inheritance. Panel A: Three-generation pedigree showing affected individuals (fully filled) all male, with carrier females (half-filled circles) transmitting the condition to approximately half their sons (affected) and half their daughters (carriers). Panel B: An affected male with all carrier daughters but no affected sons, demonstrating the absence of male-to-male transmission. Panel C: Two genetic crosses: carrier female (X^A X^a) x normal male (X^A Y) producing carrier daughters, normal daughters, affected sons, and normal sons in equal proportions; and normal female x affected male producing all carrier daughters and all normal sons. Panel D: Key features annotated: "males primarily affected," "no male-to-male transmission," "carrier females may have mild features due to variable X-inactivation." ### X-Linked Dominant X-linked dominant conditions affect both sexes but are often more severe in males—so severe that they may be lethal, explaining why some X-linked dominant conditions appear almost exclusively in females. Affected males have received the mutation from their mothers (since their fathers contributed a Y chromosome). Affected females may have received the mutation from either parent. An affected father transmits the mutant X to all daughters (who are affected) but to no sons (who receive Y). An affected mother transmits to approximately 50% of children of either sex. The excess of affected females and the severity in males distinguish this pattern. Rett syndrome, a neurodevelopmental disorder causing regression in early childhood, is almost exclusively seen in females because affected male fetuses typically do not survive. Incontinentia pigmenti, with characteristic skin findings, is similarly male-lethal. Hypophosphatemic rickets (vitamin D-resistant rickets) affects both sexes but with severity variation. --- ## Non-Mendelian Inheritance ### Mitochondrial Inheritance Mitochondria contain their own circular DNA encoding 37 genes, including subunits of the electron transport chain. Mitochondrial DNA is inherited exclusively from the mother because sperm contribute virtually no cytoplasm to the zygote. Consequently, an affected mother transmits her mitochondrial mutation to all her children, but an affected father transmits to none. A key feature of mitochondrial genetics is heteroplasmy—cells contain hundreds to thousands of mitochondria, and the proportion of mutant versus normal mitochondria can vary. This heteroplasmy explains the variable expression typical of mitochondrial diseases: individuals with more mutant mitochondria tend to be more severely affected. Tissues with high energy demands—brain, muscle, heart, retina—are most vulnerable to mitochondrial dysfunction. MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibers), and Leber hereditary optic neuropathy (sudden bilateral vision loss) exemplify mitochondrial inheritance. Panel A: Mitochondrial inheritance pedigree showing all children of an affected woman at risk (variable shading indicating variable expression), while children of an affected man are unaffected. Panel B: Inset illustrating the cellular basis of heteroplasmy with a cell containing mitochondria with varying proportions of mutant (red) and normal (green) mtDNA. Panel C: Bar graph showing that higher mutant load correlates with greater severity, with the tissues most affected (brain, muscle, heart) listed with illustrations. Panel D: Key features annotated: "maternal transmission only," "variable expression due to heteroplasmy," "high-energy tissues most affected," with threshold effect for disease manifestation. ### Genomic Imprinting Genomic imprinting creates a parent-of-origin effect on gene expression: certain genes are expressed only from the maternal or paternal copy, with the other copy silenced by epigenetic modifications (DNA methylation, histone modifications) established during gametogenesis. If the expressed copy is mutated or deleted, the silenced copy cannot compensate. The classic example involves chromosome 15q11-13. Genes in this region expressed from the paternal chromosome, when deleted or mutated, cause Prader-Willi syndrome (hypotonia in infancy, later obesity, hypogonadism, intellectual disability). The same deletion, when it affects the maternal chromosome, causes Angelman syndrome (severe intellectual disability, seizures, happy demeanor, puppet-like movements). The conditions are phenotypically distinct because different genes are affected—those expressed paternally versus those expressed maternally. Uniparental disomy (UPD), where both chromosomes come from one parent, can also reveal imprinting effects. Maternal UPD for chromosome 15 causes Prader-Willi (no functional paternal genes), while paternal UPD causes Angelman (no functional maternal genes). Beckwith-Wiedemann syndrome (overgrowth, macroglossia, omphalocele, tumor predisposition) results from various imprinting defects at chromosome 11p15. ### Trinucleotide Repeat Disorders A remarkable class of mutations involves unstable trinucleotide repeats that can expand across generations. When the number of repeats exceeds a threshold, disease results. A key feature is anticipation: repeats tend to grow during transmission, especially through the germline of one parent, so successive generations develop earlier-onset, more severe disease. Huntington disease illustrates this pattern. Normal individuals have fewer than 35 CAG repeats in the HTT gene; affected individuals have more than 40. Repeat length correlates with age of onset—more repeats mean earlier disease. Paternal transmission tends to cause larger expansions, explaining why juvenile-onset Huntington disease is usually inherited from the father. Fragile X syndrome, the most common inherited cause of intellectual disability, results from massive expansion of CGG repeats in FMR1. Normal individuals have fewer than 55 repeats; affected individuals have more than 200, which silences the gene through methylation. A premutation range (55-200 repeats) does not cause classic fragile X but is unstable and can expand to full mutation during maternal transmission. Myotonic dystrophy shows especially dramatic anticipation, with CTG repeat expansion causing congenital myotonic dystrophy when massively expanded. Friedreich ataxia, unusual among repeat disorders, is recessive—both alleles must have expanded GAA repeats. Panel A: Four-generation pedigree with Huntington disease showing repeat numbers beneath each individual (35, 42, 48, 65) and corresponding decreasing age of onset (65, 45, 30, 18 years), demonstrating anticipation. Panel B: Graph showing the correlation between repeat length and age of onset, with the threshold for disease marked. Panel C: Molecular basis showing DNA with CAG repeats at three levels: normal (short tract), premutation (intermediate), and fully expanded (long tract) alleles. Panel D: Table comparing four trinucleotide repeat disorders: Huntington (CAG, coding, gain of function), Fragile X (CGG, 5' UTR, gene silencing), Myotonic dystrophy (CTG, 3' UTR, RNA toxicity), and Friedreich ataxia (GAA, intronic, loss of function), with key features of anticipation and parent-of-origin effects annotated. --- ## Genetic Testing ### Types of Tests Genetic testing encompasses a range of technologies with different resolutions, capabilities, and appropriate applications. Selecting the right test requires understanding what each can and cannot detect. Karyotyping, the traditional cytogenetic analysis, involves culturing cells, arresting them in metaphase, and visualizing chromosomes by microscopy. It detects aneuploidy (abnormal chromosome number), large deletions and duplications (typically >5-10 Mb), and structural rearrangements like translocations and inversions. Its resolution is limited—small changes are invisible. Fluorescent in situ hybridization (FISH) uses fluorescently labeled DNA probes that hybridize to specific chromosomal regions. It can detect microdeletions too small for standard karyotyping (such as the 22q11.2 deletion causing DiGeorge syndrome) and is faster than karyotyping but only tests for specific regions determined by the probes chosen. Chromosomal microarray analysis (CMA) surveys the entire genome for copy number variations (CNVs)—deletions and duplications—with much higher resolution than karyotyping (down to ~50-100 kb). It has become a first-tier test for unexplained intellectual disability and multiple congenital anomalies. However, it cannot detect balanced rearrangements or sequence-level mutations. DNA sequencing directly reads the nucleotide sequence. Sanger sequencing, the traditional method, examines one gene at a time with high accuracy but limited throughput. Next-generation sequencing (NGS) enables parallel sequencing of multiple genes (panel), most coding regions (exome), or the entire genome. NGS detects point mutations and small indels but may miss large deletions, structural variants, or mutations in regions with poor coverage. Targeted mutation analysis tests for specific known mutations rather than searching comprehensively. It is used when a familial mutation is known or when screening populations for common mutations (such as the CFTR panel for cystic fibrosis carrier screening). Panel A: Karyotyping at lowest resolution showing G-banded chromosomes under microscopy, with capabilities (aneuploidies, large rearrangements at 5 Mb or greater resolution) and clinical indication for suspected trisomy. Panel B: FISH showing fluorescent microscopy with colored dots on chromosomes, used for detecting microdeletions such as 22q11.2 deletion in DiGeorge syndrome. Panel C: Chromosomal microarray depicted as a grid of data points showing CNV detection down to approximately 100 kb, with the note "cannot detect balanced rearrangements," indicated for unexplained developmental delay. Panel D: DNA sequencing showing a Sanger chromatogram and next-generation sequencing heatmap, with capabilities (point mutations, small indels) and indication for suspected single-gene disorders, arranged at highest resolution. ### Clinical Applications Diagnostic testing confirms a suspected genetic diagnosis in an affected individual. The clinical presentation guides test selection—a child with features of Down syndrome would receive karyotyping, while a child with suspected cystic fibrosis might undergo CFTR sequencing or mutation panel. Carrier testing identifies heterozygotes for recessive conditions. This is relevant for individuals with affected relatives or those from populations with elevated carrier frequencies. Carrier testing for conditions like cystic fibrosis, sickle cell disease, Tay-Sachs disease, and others is routinely offered during pregnancy planning. Predictive or presymptomatic testing determines whether an at-risk individual carries a mutation for a late-onset condition before symptoms develop. The paradigm is Huntington disease testing in adults at 50% risk. Such testing raises profound ethical considerations—the result cannot be undone, and there may be no preventive treatment. Genetic counseling before and after testing is essential. Prenatal testing detects genetic conditions in a fetus. Invasive methods include amniocentesis (sampling amniotic fluid) and chorionic villus sampling (CVS, sampling placental tissue). Cell-free fetal DNA testing (non-invasive prenatal testing, NIPT) analyzes fetal DNA circulating in maternal blood, screening for common aneuploidies with high accuracy and no procedural risk, though it remains a screening test requiring confirmation for positive results. Newborn screening is a public health program that tests all newborns for a panel of treatable conditions. Phenylketonuria (PKU), the first condition screened, is prevented by early dietary restriction. Most programs now screen for dozens of conditions including congenital hypothyroidism, sickle cell disease, galactosemia, and numerous metabolic disorders detectable by tandem mass spectrometry. --- ## Calculating Genetic Risk ### Punnett Squares The Punnett square is the simplest tool for calculating inheritance probabilities for single-gene traits. For a carrier × carrier cross (Aa × Aa), the square demonstrates that 25% of offspring will be affected (aa), 50% will be carriers (Aa), and 25% will be non-carrier wild-type (AA). This 1:2:1 genotypic ratio, appearing as a 3:1 phenotypic ratio when the mutation is recessive, is fundamental to Mendelian genetics. ### Bayesian Analysis Real clinical genetics often requires incorporating multiple pieces of information to refine risk estimates. Bayesian analysis provides the mathematical framework. The prior probability (before additional information) is modified by conditional probabilities based on new information to yield a posterior probability. For example, if a woman's brother has Duchenne muscular dystrophy, her prior probability of being a carrier is 50%. But if she has had three unaffected sons, this observation is more likely if she is not a carrier than if she is. Bayesian calculation incorporates this information, substantially reducing her carrier risk below 50%. ### Hardy-Weinberg Equilibrium The Hardy-Weinberg principle describes allele frequencies in a population at equilibrium. For a gene with two alleles, if p represents the frequency of the dominant allele and q represents the frequency of the recessive allele (where p + q = 1), then the genotype frequencies are: p² (homozygous dominant), 2pq (heterozygous carriers), and q² (homozygous recessive, typically affected). This principle allows calculation of carrier frequencies from disease prevalence. For cystic fibrosis, with a disease frequency of approximately 1/2,500 in Caucasians, q² = 1/2500, so q = 1/50, and the carrier frequency (2pq ≈ 2q since p ≈ 1) is approximately 1/25. Such calculations inform carrier screening recommendations. --- ## Common Genetic Disorders The landscape of genetic disorders spans the range of inheritance patterns and mechanisms discussed. Cystic fibrosis, affecting approximately 1 in 2,500 Caucasians, is autosomal recessive, caused by mutations in the CFTR chloride channel. Sickle cell disease, affecting approximately 1 in 500 African Americans, is also autosomal recessive, caused by the HbS mutation in β-globin. Duchenne muscular dystrophy, affecting approximately 1 in 3,500 males, is X-linked recessive, caused by mutations in dystrophin. Huntington disease, affecting approximately 1 in 10,000 individuals, is autosomal dominant with complete penetrance, caused by CAG expansion in HTT. Down syndrome, the most common chromosomal abnormality compatible with survival (approximately 1 in 700 live births), results from trisomy 21. Fragile X syndrome, affecting approximately 1 in 4,000 males, is X-linked with complex inheritance related to repeat expansion in FMR1. --- ## Clinical Correlations ### Genetic Counseling Genetic counselors are healthcare professionals with specialized training in medical genetics and counseling. They perform risk assessment, explain genetic concepts to patients and families, discuss testing options, interpret results, and support decision-making. The traditional approach is non-directive—providing information and support without telling patients what to choose. Increasingly, genetic counselors work in subspecialty settings (cancer genetics, prenatal, cardiovascular) and address the complexities of genomic medicine. ### Pharmacogenomics Genetic variation affects drug metabolism, efficacy, and toxicity. Pharmacogenomics aims to individualize drug therapy based on genetic profiles. CYP2C19 variants affect metabolism of clopidogrel—poor metabolizers do not convert the prodrug to its active form, leading to therapeutic failure and cardiovascular events. HLA-B*5701 testing before abacavir (an HIV medication) prevents severe hypersensitivity reactions. TPMT variants affect metabolism of thiopurine drugs—poor metabolizers experience life-threatening bone marrow toxicity at standard doses. These examples represent the leading edge of precision medicine. ### Gene Therapy Gene therapy introduces functional genes to treat genetic diseases, representing a fundamental shift from managing symptoms to correcting underlying causes. Recent successes include voretigene neparvovec (Luxturna) for inherited retinal dystrophy caused by RPE65 mutations, where a viral vector delivers the functional gene to retinal cells, restoring vision. Onasemnogene abeparvovec (Zolgensma) delivers functional SMN1 to treat spinal muscular atrophy, with dramatic improvements in survival and motor function when given early. These therapies, while costly, demonstrate that genetic diseases once thought untreatable can be addressed at their root cause. --- ## Summary - Mutations can be classified by size (point, indel, chromosomal) and effect (silent, missense, nonsense, frameshift) - Mendelian patterns: autosomal dominant, autosomal recessive, X-linked - Non-Mendelian patterns: mitochondrial, imprinting, trinucleotide repeats - Genetic testing ranges from karyotype to whole genome sequencing - Hardy-Weinberg allows calculation of carrier frequencies - Genetic counseling integrates risk assessment with ethical considerations --- ## Key Terms | Term | Definition | |------|------------| | Allele | Alternative version of a gene | | Penetrance | Proportion of individuals with genotype who express phenotype | | Expressivity | Degree to which phenotype is expressed | | Anticipation | Earlier onset in successive generations (triplet repeats) | | Imprinting | Parent-of-origin dependent gene expression | | Haploinsufficiency | One gene copy insufficient for normal function | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*