Mendelian inheritance

Disorders caused by a defect in a single gene follow the
patterns of inheritance described by Mendel and the term
mendelian inheritance has been used to denote unifactorial
inheritance since 1901. Individual disorders of this type are
often rare, but are important because they are numerous. By
2001, over 9000 established gene or phenotype loci were listed
in OMIM. Online Mendelian Inheritance in Man (TM).
McKusick-Nathans Institute for Genetic Medicine, Johns
Hopkins University (Baltimore, MD) and National Center for
Biotechnology Information, National Library of Medicine
(Bethesda, MD), 2000. World Wide Web URL:
http://www.ncbi.nlm.nih.gov/omim. Risks within an affected
family are often high and are calculated by knowing the mode
of inheritance and the structure of the family pedigree.

Autosomal dominant disorders

Autosomal dominant disorders affect both males and females.
Mild or late onset conditions can often be traced through many
generations of a family. Affected people are heterozygous for
the abnormal allele and transmit this to half their offspring,
whether male or female. The disorder is not transmitted by
family members who are unaffected themselves. Estimation of
risk is therefore apparently simple, but in practice several
factors may cause difficulties in counselling families.

Late onset disorders

Dominant disorders may have a late or variable age of onset of
signs and symptoms. People who inherit the defective gene will
be destined to become affected, but may remain asymptomatic
well into adult life. Young adults at risk may not know whether
they have inherited the disorder and be at risk of transmitting
it to their children at the time they are planning their own
families. The possibility of detecting the mutant gene before
symptoms become apparent has important consequences for
conditions such as Huntington disease and myotonic dystrophy.
Predictive genetic testing is considered in chapter 3.

Variable expressivity

The severity of many autosomal dominant conditions varies
considerably between different affected individuals within the
same family, a phenomenon referred to as variable expressivity.
In some disorders this variability is due to instability of the
underlying mutation, as in the disorders caused by
trinucleotide repeat mutations (discussed in chapter 7). In
many cases, the variability is unexplained. The likely severity in
any affected individual is difficult to predict. A mildly affected
parent may have a severely affected child, as illustrated by
tuberous sclerosis, in which a parent with only skin
manifestations of the disorder may have an affected child with
infantile spasms and severe mental retardation. Tuberous
sclerosis also demonstrates pleiotropy, resulting in a variety of
apparently unrelated phenotypic features, such as skin
hypopigmentation, multiple hamartomas and learning
disability. Each of these pleiotropic effects can demonstrate
variable expressivity and penetrance in a given family.

New mutations

New mutations may account for the presence of a dominant
disorder in a person who does not have a family history of the
disease. New mutations are common in some disorders, such as
achondroplasia, neurofibromatosis (NF1) and tuberous
sclerosis, and rare in others, such as Huntington disease and
myotonic dystrophy. When a disorder arises by new mutation,
the risk of recurrence in future pregnancies for the parents of
the affected child is very small. Care must be taken to exclude
mild manifestations of the condition in one or other parent
before giving this reassurance. This causes no problems in
conditions such as achondroplasia that show little variability,
but can be more difficult in many other conditions, such as
neurofibromatosis and tuberous sclerosis. It is also possible that
an apparently normal parent may carry a germline mutation.
In some cases the mutation will be confined to gonadal tissue,
with the parent being unaffected clinically. In others the
mutation will be present in some somatic cells as well. In
disorders with cutaneous manifestations, such as NF1, this may
lead to segmental or patchy involvement of the skin. In either
case, there will be a considerable risk of recurrence in future
children. A dominant disorder in a person with a negative
family history may alternatively indicate non-paternity.

Homozygosity

Homozygosity for dominant genes is uncommon, occurring
only when two people with the same disorder have children
together. This may happen preferentially with certain
conditions, such as achondroplasia. Homozygous
achondroplasia is a lethal condition and the risks to the
offspring of two affected parents are 25% for being an affected
homozygote (lethal), 50% for being an affected heterozygote,
and 25% for being an unaffected homozygote. Thus two out of
three surviving children will be affected.

Autosomal recessive inheritance

Most mutations inactivate genes and act recessively. Autosomal
recessive disorders occur in individuals who are homozygous
for a particular recessive gene mutation, inherited from healthy
parents who carry the mutant gene in the heterozygous state.
The risk of recurrence for future offspring of such parents is
25%. Unlike autosomal dominant disorders there is usually no
preceding family history. Although the defective gene is passed
from generation to generation, the disorder appears only
within a single sibship, that is, within one group of brothers
and sisters. The offspring of an affected person must inherit
one copy of the mutant gene from them, but are unlikely to
inherit a similar mutant gene from the other parent unless the
gene is particularly prevalent in the population, or the parents
are consanguineous. In most cases, therefore, the offspring of
an affected person are not affected.