Genetic Foundations - Code Breakers
- Gene: Basic hereditary unit; DNA segment. Allele: Variant form of a gene.
- Genotype: Genetic makeup. Phenotype: Observable traits.
- Mutation: Permanent DNA sequence alteration. Types:
- Point: Single base change.
- Frameshift: Insertion/deletion, shifts reading frame.
- Missense: Codes different amino acid.
- Nonsense: Creates premature stop codon.
- Penetrance: Proportion of individuals with genotype expressing phenotype.
- Expressivity: Degree of phenotypic expression.
- Genetic Disorder Types: Single gene (Mendelian), Chromosomal, Multifactorial, Mitochondrial.
⭐ Pleiotropy: one gene influences multiple phenotypic traits.
Mendelian Inheritance - Family Traits
- Comparison of Mendelian Inheritance Patterns
| Feature | Autosomal Dominant (AD) | Autosomal Recessive (AR) | X-linked Recessive (XLR) | X-linked Dominant (XLD) |
|---|---|---|---|---|
| Inheritance | Vertical; affected parent has affected child | Horizontal; skips generations; consanguinity common | Diagonal; no male-to-male transmission; carrier females | Vertical; no male-to-male; affected fathers have all affected daughters |
| Recurrence Risk (affected parent) | 50% (heterozygous parent) | 25% (carrier parents) | Affected father: all daughters carriers, no sons affected. Carrier mother: 50% sons affected, 50% daughters carriers. | Affected father: all daughters affected, no sons affected. Affected mother: 50% offspring affected. |
| Sex Predilection | Equal | Equal | Males > Females | Females > Males (often lethal in males) |
| Examples | Marfan, Huntington, Achondroplasia, NF1 | Cystic Fibrosis, Sickle Cell, PKU, Tay-Sachs, Albinism | Hemophilia A/B, Duchenne MD, G6PD deficiency | Vitamin D-resistant Rickets, Rett Syndrome |
- *Variable Expressivity*: Trait severity varies (e.g., Neurofibromatosis 1).
- *Incomplete Penetrance*: Not all individuals with genotype express phenotype (e.g., BRCA1/2).
📌 Mnemonic (AD): All Dominant Hereditary Maladies Need Attention (Achondroplasia, Huntington's, Marfan's, Neurofibromatosis, Adult Polycystic Kidney Disease).
⭐ New mutations are a significant cause of Autosomal Dominant disorders like Achondroplasia and Duchenne Muscular Dystrophy (1/3rd of cases).
Chromosomal Chaos - Number Games
- Numerical Abnormalities:
- Aneuploidy (abnormal chromosome number):
- Trisomies (2n+1): 📌 "Drinking at 21 (Down), Election at 18 (Edwards), Puberty at 13 (Patau)"
- Down S. (Trisomy 21): Intellectual disability, flat facies, single palmar crease, Brushfield spots.
- Edwards S. (Trisomy 18): Rocker-bottom feet, clenched hands, micrognathia, low-set ears.
- Patau S. (Trisomy 13): Cleft lip/palate, polydactyly, microcephaly, holoprosencephaly.
- Monosomy (2n-1): Turner S. (45,XO): Female; short stature, webbed neck, ovarian dysgenesis, coarctation of aorta.
- Trisomies (2n+1): 📌 "Drinking at 21 (Down), Election at 18 (Edwards), Puberty at 13 (Patau)"
- Sex Chromosome Aneuploidy:
- Klinefelter S. (47,XXY): Male; tall, gynecomastia, testicular atrophy, infertility.
- Aneuploidy (abnormal chromosome number):
- Structural Abnormalities:
- Deletions: Cri-du-chat S. (5p-): Cat-like cry, microcephaly, intellectual disability.
- Translocations:
- Robertsonian: Fusion of 2 acrocentric chr. (e.g., 13,14,15,21,22); can cause Down S.
- Philadelphia Chr.: t(9;22) (BCR-ABL) → CML.
⭐ Maternal age is the most significant risk factor for Trisomy 21.
Atypical Inheritance & Diagnosis - Tricky Genes & Tools
- Multifactorial Inheritance: Multiple genes + environment (e.g., HTN, DM, Cleft lip/palate). Threshold model: liability must exceed threshold.
- Non-Classic Inheritance:
- Trinucleotide Repeats: Anticipation (earlier/severe onset). 📌 "Try Hunting for Fragile Myce": Huntington (CAG), Fragile X (CGG), Myotonic Dystrophy (CTG).
- Mitochondrial: Maternal transmission (e.g., LHON).
- Genomic Imprinting: Gene expression depends on parental origin (e.g., Prader-Willi/Angelman - del 15q11-13).
- Gonadal Mosaicism: Germline mutation.
- Diagnosis:
- Tests: Karyotyping, FISH, PCR, Microarrays, NGS.
- Prenatal: Amniocentesis, CVS, NIPT.
⭐ Fragile X syndrome is the most common inherited cause of intellectual disability.
High‑Yield Points - ⚡ Biggest Takeaways
- Autosomal Dominant: Vertical transmission, 50% offspring risk; often structural protein defects (e.g., Marfan).
- Autosomal Recessive: Horizontal transmission, 25% offspring risk; typically enzyme deficiencies (e.g., Cystic Fibrosis).
- X-Linked Recessive: Primarily affects males; carrier females; no male-to-male transmission (e.g., Duchenne).
- Mitochondrial Inheritance: Exclusively maternal transmission to all offspring; affects high ATP-demand tissues.
- Trinucleotide Repeat Disorders: Exhibit anticipation; severity ↑ with generations (e.g., Huntington, Fragile X).
- Genomic Imprinting: Gene expression depends on parental origin (e.g., Prader-Willi/Angelman - 15q deletion).
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