Genetics of Disease and Applies Genetics in Medicine

RAME model

diseases are highly heterogenous, with hundreds or thousands of rare mutations causing individual cases of disease

Allelic heterogeneity

Different mutations in the same gene produce the same phenotype

Locus heterogeneity

Mutations at different genes or chromosomal loci can produce a single phenotype

Modifier genes

genes that influence the expression of other genes and/or the phenotypic manifestation of a mutation; epistasis

Pleiotropy

A single gene having multiple effects on an individuals phenotype

Penetrance/expressivity

varying proportion of phenotype observed given a particular genotype

Heritability

the proportion of variance of a phenotype in a population that can be attributed to genotypic differences

Inheritance

The process by which physical and biological characteristics are transmitted from the parent (or parents) to the offspring

CDCV model

most disease susceptibility can be attributed to 10-20 specific loci; small effects of risk alleles with low penetrance

Infinitesimal Loci model

the idea that many small genetic loci, or Mendelian loci, contribute to a trait's variation, rare variants or environmental triggers push them over the edge; implies a threshold

Epigenetics

the study of influences on gene expression that occur without a DNA change

Epistasis

A type of gene interaction in which one gene alters the phenotypic effects of another gene that is independently inherited

Histone/DNA methylation

the condensing of chromatin structure (heterochromatin), prevents transcription; decreased expression

Histone acetylation

The attachment of acetyl groups to certain amino acids of histone proteins; increases expression

Imprinting

form of epigenetic inheritance where the regulation of a gene or chromosomal region is dependent on the sex of the transmitting parent

Screening sensitivity

-How well the screening identifies those with disorder (want to have as close to 100%)
-you catch everyone that has the disorder
-want to have a lot of true positives
# of true positives/(# of true positives + # of false negatives)

Screening specificity

-How well a screening will filter out those that don't have a disorder
-if test is too sensitive it may not be specific enough
-(you don't want too many true positives)
# of true negatives/(# of false positives + # of true negatives)

Principles of Population Screening

1. Disease should be relatively common and serious (Cost-benefit analysis)
2. There should be pre-natal diagnostics or treatments.
3. The test should be "acceptable" to population (easy, affordable).
4. Test should be valid and reliable.
5. The resources for diagnosis and treating the disease should be accessible.

Chorionic villus sampling

sampling of placental tissue for microscopic and chemical examination to detect fetal abnormalities

Types of newborn blood screenings

Phenylketonuria
Galactosemia
Hypothyroidism
Hemoglobinopathies
Cystic fibrosis
Maple syrup urine disease
Tay-Sachs disease

Despite known genetic involvement (high heritability) for many complex diseases...

...there are frequently no known polymorphisms that are helpful in determining risk

Genetic Counseling

the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions of disease

Genetic counseling integrates

- interpretation of family and medical histories to assess the chance of disease occurrence or recurrence
- education about inheritance, testing, management, prevention, resources, and research
- counseling to promote informed choices and adaptation to the risk or condition