Biology Reference
In-Depth Information
have hearing loss increases with age. Thus, penetrance may be close to zero
at 10 years of age, 0.3 at 20 years of age, 0.7 at 30 years of age, and 1.0 at
50 years of age. The degree of penetrance needs to be taken into account
when calculating recurrence risks for individuals who have relatives with
an autosomal dominant disease. Incomplete penetrance and/or variable
expression among family members suggests that other genes and environ-
mental factors are contributing to the phenotype.
An offspring with an autosomal dominant disorder may sometimes have
two unaffected parents. As discussed above, this situation is observed with
incomplete penetrance (a value less than 1.0). If, in addition, the affected
offspring has no affected relatives, then the possibility of a new mutation
must be considered. For example, more than 80% of cases of achon-
droplasia (short-limbed dwarfism) are new mutations in germ cells (sperm
or ova). Occasionally, unaffected parents have more than one offspring with
a dominant disorder. A likely explanation in this situation is germline
mosaicism, which occurs if the mutation arose during the embryonic life of
one of the parents in a cell destined to be a germ cell. As a result, some (or
possibly all) of the germ cells carry the mutation.
1.2.2 Autosomal Recessive Inheritance
The mode of inheritance of a disorder is autosomal recessive if the abnor-
mal phenotype is expressed only in individuals who have two copies of the
deleterious allele. Heterozygotes are not affected and are often called car-
riers. Assuming complete penetrance, the probability that a child of carrier
parents will be affected is one quarter; the probability that an unaffected
sibling is a carrier is two thirds (Fig. 1.1). If a hearing impaired child of
normal hearing parents has an affected sibling or the parents are related,
then the etiology is most likely to be a deleterious gene with the mode of
inheritance being autosomal recessive. Alternatively, if a known environ-
mental insult such as an infectious agent or a drug is documented, then the
presence of a deleterious gene is less likely. However, the possibility of
recessive inheritance must always be considered. Note that family history
is quite likely to be negative with a recessive disorder because the abnor-
mal allele may be passed from one (unaffected) carrier to the next for many
generations before a couple, who by chance both carry the same deleteri-
ous allele, has an affected child. Recessive inheritance probably explains
most cases of profound sensorineural hearing loss when family history
is negative, and there is no known environmental factor that could be
responsible.
It is not uncommon for deaf individuals to marry one another. However,
the underlying causes of their deafness may be different, even though both
may have recessive deafness. If both are homozygous for the same delete-
rious allele, then all their children will also be homozygous for this allele.
However, if deleterious alleles for different genes are responsible for the
