Transcript Lctures Clinical genetics – 7

EMPIRIC RISK
Using Mendel’s laws, it is possible to predict the risk that a single gene
trait will recur in a family if one knows the mode of inheritance—such as
autosomal dominant or recessive. To predict the chance that a
multifactorial trait will occur in a particular individual, geneticists use
empiric risks, which are based on incidence of disease/disorder in
a specific population.
Empiric risk is not a calculation, but a population statistic based on
observation
Incidence is the rate at which a certain event occurs, that is the
number of new cases of a particular disorder diagnosed per year in a
population of known size.
Prevalence is the proportion or number of individuals in a population who
have a particular disorder at a specific time.
Empiric risk increases with:
•the severity of the disorder,
•the number of affected family members,
•and how closely related a person is to affected individuals.
As an example, consider using empiric risk to predict the likelihood of a
child being born with a neural tube defect (NTD). In the United States,
the overall population risk of carrying a fetus with an NTD is about 1 in
1,000 (0.1 percent). For people of English, Irish, or Scottish ancestry, the
risk is about 3 in 1,000. However, if a sibling has an NTD, no matter
what the ethnic group, the risk of recurrence increases to 3 percent, and
if two siblings are affected, the risk to a third child is even greater. By
determining whether a fetus has any siblings with NTDs, a genetic
counselor can predict the risk to that fetus, using the known empiric risk.
Because empiric risk is based solely on observation, we can use it to
derive risks for disorders with poorly understood transmission
patterns
Pyloric stenosis is an overgrowth of muscle at the juncture between the
stomach and the small intestine. It is five times more common among
males than females. The condition must be corrected surgically shortly
after birth, or the newborn will be unable to digest foods. Empiric data
show that the risk of recurrence for the brother of an affected
brother is 3.8 percent, but the risk for the brother of an affected
sister is 9.2 percent. An empiric risk, then, is based on real-world
observations— the mechanism of the illness or its cause need not
be known.
EMPIRIC RISK
1. Empiric risk is not calculated, but is an observed population statistic.
2. Empiric risk is used to predict recurrence of a multifactorial trait in a family.
3. Empiric risk increases with severity of the trait, number of affected
relatives, sex of family members, and increasing relatedness to an affected
individual.
HERITABILITY
designated H, estimates the proportion of the phenotypic variation
for a particular trait that is due to genetic differences in a certain
population
at a certain time. The distinction between empiric risk and heritability
is that empiric risk could result from non-genetic influences, whereas
heritability focuses on the genetic component of a trait.
Heritability equals 1.0 for a trait whose variability is completely the
result of gene action, such as in a population of laboratory mice whose
environment is controlled. Without environmental variability, genetic
differences determine expression of the trait in the population.
Variability of most traits, however, reflects a combination of
differences among genes and environmental components.
Heritability changes as the environment changes. For example, the
heritability of skin color would be higher in the winter months, when
sun exposure is less likely to increase melanin synthesis. The same
trait may be highly heritable in two populations,
COEFFICIENT OF RELATEDNESS
The coefficient of relatedness indicates the proportion of genes relatives share
The coefficient of relatedness increases as more closely related individuals are
compared
A parent and child share 50 percent of
their genes, because of the mechanism of
meiosis. Siblings share on average 50 percent
of their genes, because they have a
50 percent chance of inheriting each allele for
a gene from each parent. Genetic counselors
use the designations of primary (1°), secondary
(2°), and tertiary (3°) relatives when
calculating risks
For extended or complicated pedigrees, the
value of 1/2 or 50 percent between siblings
and between parent-child pairs can be used
to trace and calculate the percentage of genes
shared between people related in other ways.
of the genome shared for first cousins
separated by generations, described as
“removed” by one or more generations.
HALLMARKS FOR MULTIFACTORIAL INHERITANCE
The disease can occur in isolation, with affected children born to unaffected parents.
Although familial aggregation is also common (i.e., there may be multiple cases in the
same family), there is no clear Mendelian pattern of inheritance.
•Environmental influences can increase or decrease the risk of the disease.
•The disease occurs more frequently in one gender than in the other, but it is not a sexlimited trait. In addition, first-degree relatives of individuals belonging to the more
rarely affected gender have a higher risk of bearing the disease (International
Commission on Radiological Protection, 2000).
•The concordance rates in monozygotic and dizygotic twins contradict Mendelian
proportions. A concordance rate is a measure of the rate at which both twins bear a
specific disease (Mossey, 1999; Griffiths et al., 1999).
•The disease occurs more frequently in a specific ethnic group (i.e., Caucasians,
Africans, Asians, Hispanics, etc.).
Most affected children have normal parents. This is true of diseases and quantitative
traits. Most geniuses come from normal parents, most mentally challenged come from
normal parents.
Recurrence risk increases with the number of affected children in a family.
Recurrence risk increases with severity of the defect. A more severely affected
parent is more likely to produce an affected child.
Consanguinity slightly increases the risk for an affected child.
Risk of affected relatives falls off very quickly with the degree of relationship. Contrast
this with autosomal dominant inheritance with incomplete penetrance, where the
recurrence risk falls off proportionately with the degree of relationship.
If the two sexes have a different probability of being affected, the least likely sex, if
affected, is the most likely sex to produce an affected offspring.