than 2 ng/ml if measured 24 hours or more after
birth. The concentration of 17-hydroxyprogesterone
is higher in the immediate newborn period (less than
24 hours), in premature infants, and in ill term
infants, although, even in these newborns, the
concentration is rarely as high as 20 ng/ml (Miller
1997). Using 20 ng/ml as the critical value yields
very large likelihood ratios for screen-positive study
results. The likelihood ratios exceed the threshold
likelihood ratio for followup as calculated using the
prevalence of severe 21-hydroxylase deficiency
mentioned above and any reasonable value for
P[rejection]. Additionally, a critical value of 20
ng/ml yields a high sensitivity for the detection of
severe 21-hydroxylase deficiency. Thus, the use of
17-hydroxyprogesterone as a screening study for
severe 21-hydroxylase deficiency is justified. The
study is included in the set of newborn screening
studies performed in a number of states in the United
States.
Screening for adult-onset genetic disease
Diagnostic studies are available for a number of
genetic disorders that present in adulthood (Ravine
and Cooper 1997). Currently, none of the studies is
used to screen the general population or even at-risk
subpopulations; the studies are used exclusively in
the diagnostic evaluation of individuals determined
to be at risk on the basis of family history. The are
two major reasons for this. The first reason is that,
for some of the disorders, there are no effective
measures for the prevention of the onset of clinical
disease or effective therapy for the amelioration of
the disease. The second reason is that most of the
disorders show substantial inter-family variability in
the phenotypic expression of the disorder even when
the genotypic forms are identical. Consequently, it
would not be possible to distinguish screen-positive
individuals in whom the disorder would be serious
from those in whom the clinical effects would be
slight.
REPRODUCTION AND GENETIC DISEASE
There are two primary medical goals for human
reproduction as far as genetic disease is concerned.
First, couples contemplating having a child must be
aware of the risks of producing a child with a
genetic disorder. Second, affected offspring must be
identified while
in utero
so that the parents can make
a decision about bringing the pregnancy to term.
Risk assessment and carrier detection
The risk of having a child with a particular
genetic disorder depends upon the form of expres-
sion of the disease, i.e. whether it is dominant or
recessive, upon the genotype of the parents, and
upon the rate at which mutations causing the disease
arise
de novo
(Table 10.6). The probabilities depend
upon a knowledge of the genotypes of the parents.
While the parental genotypes for a dominant disease
are made manifest by the presence or absence of the
disease, the genotypes for a recessive disease are
not. A parent who does not have a recessive disorder
may be homozygous for the normal gene or he or
she may be heterozygous for the disease-producing
gene. Individuals who are heterozygous for a reces-
sive disorder are often referred to as carriers and the
laboratory evaluation of the heterozygous genotype
is called carrier detection. At present, there are no
screening programs for carrier detection in the
general population. Evaluation of carrier status is
limited to individuals who have a family history for
the disease or who are members of subpopulations
that have a high carrier prevalence. One such at-risk
subpopulation is the Ashkenazi Jews. Approxi-
mately 3 in every 100 members of this subpopulation
are carriers for Tay-Sachs disease. Therefore, in the
absence of a positive family history, the probability
Genetic Disease
10-12
Table 10.6
Probability of parenting a child expressing a genetic
disorder ( -, normal gene; m, mutant gene)
Mutant Gene Genotype Probability
Expression of Parents
Dominant
- -
- -
mutation rate
- -
- m 0.5
- m - m 0.25 homozygous
0.5 heterozygous
Recessive - -
- -
zero
- -
- m mutation rate
- m - m 0.25
m m - m 0.5
m m m m 1
X-linked
%
-
&
- -
%
mutation rate
&
zero
%
-
&
- m
%
0.5
&
mutation rate
%
m
&
- -
%
mutation rate
&
mutation rate
%
m
&
- m
%
0.5
&
0.5
