05: Patterns of Inheritance Flashcards
What is a genotype?
The genetic composition at a given location (allele) in the genome.
What is a phenotype?
The observable expression of a genotype (morphological, clinical, biochemical).
What is penetrance?
The probability that an indivdiaul carrying a specific genotype will express ANY phenotype (all or none). Complete = 100%, incomplete = <100%.
What are the reasons behind reduced penetrance?
- Developmental (genetic change not sufficient by itself to cause phenotype; other factors necessary)
- Time-related (findings have onset in older age; e.g., Huntington disease, colon cancer)
- Sex-limited (e.g., male pattern baldness)
What is expressivity?
The degree to which a phenotype is apparent, and in what manner. Due to variable organ involvement (pleiotropy: one change causes multiple effects).
Example: Marfan syndrome can be variable (severe to mild) or consistent.
Intrafamilial variability can result from modifier genes, environment, stochastics; interfamilial variability adds in the possibility of allelic heterogeneity (different mutations in same gene cause similar phenotype; e.g., forms of sickle cell disease) and locus heterogeneity (different mutations in different genes causing similar phenotypes; e.g., BRCA1 & 2).
What is phenotypic heterogeneity?
Mutations within the same gene leading to different phenotypes (e.g., hemoglobinopathies: hemolysis vs. cyanosis).
What is pleitropy?
One genetic change having a wide range of effects in multiple organ systems (e.g., Marfan syndrome, velocardiofacial syndrome).
What are the various modes of inheritance?
- Autosomal recessive
- Autosomal dominant
- X-linked
- Mitochondrial inheritance
- Multifactorial
What are the pedigree symbols for male, female, pregnancy, affected, deceased, carrier and consanguinity?
What are the degrees of relationships/inheritance-shared gene percentages?
- 1st degree (parents, siblings, children): 50%
- 2nd degree (grandparents, aunts/uncles, niece/nephew, grandchildren): 25%
- 3rd degree (cousins): 12.5%
Describe the characteristics of autosomal dominant conditions.
- Affected person usually has at least one affected parent.
- Affects both sexes equally.
- Transmitted by either sex.
- Child of affected parent has 50% risk of inheriting the disease.
Ask yourself: Males and females equally affected? Present in every generation? Children of affected parents have 50% chance of getting it?
Exceptions: de novo mutation, reduced penetrance (gender-specific?), variable expressivity, germline mosaicism (genetic change confined to gonads of the parent, not in somatic cells; children will have the mutation in somatic cells)
Describe the characteristics of an autosomal recessive condition.
- Affected individuals usually born to unaffected parents
- Affects either sex equally
- Observed more frequently with consanguinity
- 25% risk of having an affected child if both parents are carriers
Ask yourself: Does it skip generations? Are males and females equally affected? Does it occur more often with consanguinity?
Examples: CF, sickle cell, PKU, hemochromatosis
Describe the characteristics of an X-linked recessive condition.
- Usually affects males only
- Affected males usually born to unaffected parents
- May have other affected male relatives on the maternal side of family
- No male-to-male transmission
Ask yourself: Are only males affected? Is there no male-to-male transmission? Are carrier females asymptomatic or mild?
Affected females may be due to unfavorable lyonization (X-inactivation) or X0 chromosome (Turner’s syndrome), or homozygous (for common trait such as red-green color blindness; due to uniparental isodisomy of maternal X)
Examples: Duchenne muscular dystrophy
Describe the characteristics of an X-linked dominant condition.
- Heterozygous females affected
- Males often more affected, but not always
- Some XLDs are male lethal (pedigree shows no affected males or females > males (2:1) or increased number of miscarriages)
Example: Craniofrontonasal dysplasia
Describe the characteristics of mitochondrial inheritance.
- Exclusively maternally inherited
- Phenotype dependent on percentage of abnormal mitochondria per cell (heteroplasmy) and energy requirement of cell (energy-dependent organs more susceptible: CNS, heart, muscle)
- Presentation: can affect any organ
