VI. How do you recognize the diversity of common genetic conditions?
A. Recognizing patterns of inheritance
1. Chromosomal
2. Mendelian
Autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, modifiers, expressivity, penetrance, anticipation (triplet repeats), loss of function, gain of function, dominant negative effects, polygenetic
3. Non-Mendelian
mitochondrial, imprinting, uniparental disomy (UPD), multifactorial, heritability, teratogens, somatic mutations
B. Pedigree analysis and risk assessment
1. How to take an appropriate family history
2. How to construct a pedigree
3. Risk assessment
C. Common Genetic Disorders (complete list in attachment)
1. Chromosomal
Disorders Principles exemplified
Down syndrome Balanced translocations and risk for unbalanced offspring
22q11.2 deletion Small deletion with dominant inheritance, variable expressivity
2. Autosomal dominant (AD)
Disorders Principles exemplified
Neurofibromatosis type 1 high expressivity, allelic heterogeneity, loss of function, average fitness with 50% new mutation rate
Marfan high expressivity, allelic heterogeneity, gain of function, higher fitness with 25% new mutation rate
Osteogenesis imperfecta high expressivity, allelic and locus heterogeneity, dominant negative, loss of function, germline mosaicism
Achondroplasia low expressivity, gain of function, no allelic or locus heterogeneity, lethal double dominant, lower fitness with 75% new mutation rate, paternal age affect, germline mosaicism
Cancer syndromes gain and loss of function, two hit hypothesis, cell dysregulation
Huntington anticipation, toxic gain of function, non-lethal double dominant, high fitness with negligible new mutation rate
3. Autosomal recessive (AR)
Disorders Principles exemplified
Cystic fibrosis loss of/decreased function, allelic heterogeneity, mutation specific drug development, newborn screening)
Hemoglobinopathies loss of function, gain of function, developmental expression and regulation of globin genes, heterozygote advantage
Hemochromatosis high carrier rate and pseudodominance, presymptomatic state, decreased penetrance, allelic heterogeneity
Inborn errors of metabolism loss of function, locus and allelic heterogeneity, vitamin cofactor deficiencies, toxic metabolites, loss of energy, storage disorders
Spinal muscular atrophy loss of function, pseudogenes
Ciliopathies loss of function, locus and allelic heterogeneity
4. X-linked recessive (XLR)
Disorders Principles exemplified
G6PD loss of function, environmental exposures
Fragile X loss of function, toxic gain of function, anticipation, premutation symptoms
Duchenne loss of function; gene deletions and duplications; high new mutation rate ~1/3 (Haldane’s rule), health risks to female carriers
OTC deficiency loss of function; environmental exposures; symptomatic female carries, skewed X-inactivation
5. X-linked dominant (XLD)
Disorders Principles exemplified
Hypophosphatemic rickets loss of function, males and females affected
Incontentia pigmenti loss of function, X-inactivation, male lethality
Rett syndrome loss of function, male lethality, primarily new mutation from male germline
6. Mitochondrial
Disorders Principles exemplified
LHON loss of function, heteroplasmy, environmental exposures
MELAS loss of function, heteroplasmy, contribution to common disease (diabetes, deafness)
7. Imprinting/UPD
Disorders Principles exemplified
Angleman/Prader-Willi loss of imprinted genes, multiple mechanisms
8. Teratogens
Class of teratogen Exemplar agents
Drugs alcohol, tobacco, cocaine
Medications folate antagonists, lithium, thalidomide, warfarin
Environmental TORCH infections, radiation
Dietary iodide, folate, vitamin A
Maternal conditions diabetes, PKU, epilepsy
9. Multifactorial
Class of condition Exemplar conditions
Neurologic autism, intellectual disability, psychiatric disorders
Birth defects neural tube defects, cleft lip/palate
Adult onset health issues type 2 diabetes, obesity, hypertension, coronary artery disease
10. Somatic Mutations and Mosaicism
Disorders Principles exemplified
Osteogenesis imperfecta Germline mosaicism
Hypomelanosis of Ito Somatic mosaicism, lines of Blaschko
Cancer Somatic mutations