Empiric risk is not a calculation, but a population statistic based on observation

1. 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

2. 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.

3. 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.

5. 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.

6. EMPIRIC RISK • Empiric risk is not calculated, but is an observed population statistic. • Empiric risk is used to predict recurrence of a multifactorial trait in a family. • Empiric risk increases with severity of the trait, number of affected relatives, sex of family members, and increasing relatedness to an affected individual.

7. 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.

9. 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,

10. 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

11. 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.

12. 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 sex-limited 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.).

13. 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.