AUTOSOMAL DISORDER

There are 44 autosomes in Man comprising 22 homologous pairs of chromosomes. Upon each
chromosome, the genes have a strict order, each gene occupying a distinct locus in unison
with its counterpart of maternal or paternal origin.

Alleles are alternative forms of genes which arise by mutation, normal types being referred to
as 'wild'. If both members of a gene pair are identical then the individual is described as being
homozygous, whereas if they are different, they are said to be heterozygous.

Gene-specified characteristics are termed traits. There are three types of disorder depending
on the expression of traits:

• autosomal dominant: trait is seen in the heterozygote

• autosomal recessive: trait is seen only in homozygote
• autosomal codominant: effect of both alleles seen in heterozygote

EXAMPLES

The most common autosomal disorders are:

disorder type - incidence/1000 births

• dominant otosclerosis dominant - 3

• familial hypercholesterolaemia dominant - 2
• adult polycystic kidney disease dominant - 1
• cystic fibrosis recessive - 0.5
• recessive mental retardation recessive - 0.5
• multiple exostoses dominant - 0.5
• Huntington's disease dominant - 0.5
• neurofibromatosis dominant - 0.4

TYPES of AUTOSOMAL INHERITANCE:

Autosomal dominant inheritance is characterised by manifestation of the disorder in either the

homozygote or the heterozygote that carries the allele.

There would be expected to be a segregation ratio of 1:1 in the offspring of an affected

heterozygote and a normal partner. Hence, more offspring tend to be affected than in
autosomal recessive disorders.

As with autosomal recessive disorders, both sexes may be affected, but, there may be
different degrees of severity - variable expression - between individuals.

Rarely, an individual with a mutant gene may have a normal phenotype. This is termed 'non-
penetrance'. The gene and trait may still be transmitted to the individual's offspring.

About 2200 autosomal dominant traits are known to date. They tend to be defects of carrier,
structural or receptor proteins. The most common autosomal dominant diseases are:

disorder incidence/1000 births

• dominant otosclerosis 3
 • familial hypercholesterolaemia 2
• adult polycystic kidney disease 1
• multiple exostoses 0.5
• Huntington's disease 0.5
• neurofibromatosis 0.4
• myotonic dystrophy 0.2
• congenital spherocytosis 0.2
• polyposis coli 0.1
• dominant blindness 0.1
• dominant congenital deafness 0.1

AUTOSOMAL DOMINANT DIORDERS

A list of some autosomal dominant disorders is presented below:

• achondroplasia
• antithrombin III deficiency
• Ehlers-Danlos syndrome
• Gilbert's disease
• hereditary haemorrhagic telangiectasia
• hereditary elliptosis, hereditary spherocytosis
• Huntington's disease
• idiopathic hypoparathyroidism
• intestinal polyposis
• marble bone disease
• Marfan's syndrome
• neurofibromatosis
• polycystic kidney disease (adult)
• protein C deficiency
• osteogenesis imperfecta
• Treacher Collins syndrome
• tuberous sclerosis
• Von Willebrand's disease

AUTOSOMAL RECESSIVE

A list of some diseases that are associated with autosomal recessive inheritance is presented
below:

• oculocutaneous albinism
• alkaptonuria
• Bartter's syndrome
• cystic fibrosis
• endemic goitrous cretinism
• familial amaurotic idiocy
• galactosaemia
• Gaucher's disease
• glycogen storage disease
• phenylketonuria
• Wilson's disease
• xeroderma pigmentosa
AUTOSOMAL CODOMINANT

Autosomal codominant inheritance is defined by the ability to detect either or both of two
alleles in an individual. The two fragments can also be followed through the family pedigree.
Hence, the pedigree pattern of human codominant traits resembles that of autosomal
dominant inheritance except that both alleles can be distinguished.

Some examples of human codominant traits include:

• blood groups: ABO, Duffy, Kell, Kidd, MNS, Rhesus

• red cell enzymes: acid phosphatase, adenylate kinase
• serum proteins: haptoglobulins
• cell surface antigen: human leucocyte antigen (HLA)

Autosomal codomominant inheritance can be demonstrated if consider ABO blood groups:

• if two persons with AB blood type have children, the children can be type A, type B, or
type AB
• the possible phenotypes are
o A, AB and B
o there is a 1A:2AB:1B phenotype ratio - this compares with a 3:1 phenotype
ratio found when one allele is dominant and the other is recessive

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A gene can exist in several different forms called alleles. (Think of the gene as "ice cream" and
the alleles as "chocolate, vanilla, coffee, pistachio" or whatever). Every person inherits one copy
of a gene from each parent, and so has only two alleles, even if more than two alleles exist for
that gene.

A *dominant* allele is one that masks the expression of a *recessive* allele. For example, in
humans the allele coding for a little "Widow's Peak" (a pointy bit of hair coming down onto the
forehead) is dominant
to the allele coding for a straight hairline across the forehead. We'll call the Widow's Peak allele
(W) and the straight hairline allele (w).

A person who inherits two copies of W (genotype WW) will have a Widow's peak, as will a person
who inherits one copy of each of the alleles (genotype Ww), because W masks the expression of
w. A person who has the genotype ww will have a straight hairline.

Now, back to the autosomal genetic disorders. An autosomal gene is one that occurs on one of
the 22 pairs of autosomes (i.e., the chromosomes that are not the X and/or Y chromosomes that
are involved in sex determintion). That's all that "autosomal" means.

If an autosomal genetic disorder is *dominant* (X), only then will you get the 75% expression in
the cross you describe. If the condition is recessive (x), then a cross between a heterozygote
(Xx) and a homozygote (XX; unaffected) will give 100% unaffected offspring, 50% of whom will be
carriers of the condition.

I hope this helps explain the situation more clearly.

An X-linked gene is one that is located on the X chromosome. And just as with an autosomal
trait, the dominant version will *mask* the expression of the recessive one. This can get very
complicated, so if you need more information on how X-linked traits are inherited differently by
males and females (mammals), then please see my Gentics notes here:

http://www.bio.miami.edu/dana/250/25008_5.html

 In general, one would expect to see the following trends

in pedigrees:
 autosomal dominant trait:
• does not skip generations (unless this is a trait with
low penetrance, which we'll discuss for the *next*
exam)
• no difference in expression between genders.
 autosomal recessive trait:
• tends to skip generations
• no difference in expression between genders
• matings between expressing individuals should
produce 100% expressing offspring
• expression incidence increases with consanguinous
marriages.
 X-linked dominant trait:
• tends not to skip generations
• expressing males must have expressing mothers
• expressing female usu. yield 50:50 expressing
offspring.
• expressing female must have male OR female parent
expressing.
• expressing male will have 100% expressing daughters,
and 0% expressing sons.
 X-linked recessive trait
 • tends to skip generations
• most affected individuals will be male
• expressing female must have expressing father and
either heterozygous or expressing mother.
• An expressing female will yield 100% expressing
sons.
*****************************************************************

X-linked diseases are single gene disorders that reflect the presence of defective genes
on the X chromosome. This chromosome is present as two copies in females but only as
one copy in males.

The inheritance patterns of X-linked diseases in family pedigrees are complicated by the
fact that males always pass their X chromosome to their daughters but never to their
sons, whereas females pass their X chromosomes to daughters and sons with equal.

Like autosomal single gene disorders, X-linked diseases can be either recessive or
dominant. X-linked recessive diseases include red-green colour blindness, haemophilia
and the Duchenne and Becker forms of muscular dystrophy (both of which involve
mutations in the DMD gene). These diseases are much more common in males than
females because two copies of the mutant allele are required for the disease to occur in
females, while only one copy is required in males.
The inheritance pattern of an X-linked recessive disease has the following characteristics:

• The vast majority of affected individuals are male.

• Affected males never pass the disease to their sons because there is no male-to-
male transmission of the X chromosome.
• Affected males pass the defective X chromosome to all of their daughters, who
are described as obligate carriers. This means they carry the disease-causing allele but
generally show no disease symptoms since a functional copy of the gene is present on
the other chromosome.
• Female carriers pass the defective X chromosome to half their sons (who are
affected by the disease) and half their daughters (who are therefore also carriers). The
other children inherit the normal copy of the chromosome.
• The overall pattern of the disease is therefore characterised by the transmission
of the disease from affected males to male grandchildren through carrier daughters, a
pattern sometimes described as a 'knight's move'.
• Affected females, with two deficient X chromosomes, are the rare products of a
marriage between an affected male and a carrier female. However, manifesting carrier
females (with one deficient X chromosome and one normal one) may arise if there is a
chromosome disorder or a problem with X-chromosome inactivation.
X-linked dominant diseases are very uncommon, but some inherited forms of rickets are
transmitted in this manner. Unlike the recessive diseases discussed above, the frequency
of X-linked dominant diseases is similar in males and females. However, the absence of
male-to-male transmission distinguishes X-linked dominant diseases from autosomal
dominant diseases, in which both sexes are also equally affected.

http://en.wikipedia.org/wiki/Genetic_disorder

Multifactorial and polygenic (complex) disorders

Genetic disorders may also be complex, multifactorial or polygenic, this means that they are
likely associated with the effects of multiple genes in combination with lifestyle and
environmental factors. Multifactoral disorders include heart disease and diabetes. Although
complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance.
This makes it difficult to determine a person’s risk of inheriting or passing on these disorders.
Complex disorders are also difficult to study and treat because the specific factors that cause
most of these disorders have not yet been identified.

On a pedigree, polygenic diseases do tend to “run in families”, but the inheritance does not fit
simple patterns as with Mendelian diseases. But this does not mean that the genes cannot
eventually be located and studied. There is also a strong environmental component to many of
them (e.g., blood pressure).

• asthma
• autism
• autoimmune diseases such as multiple sclerosis
• cancers
• cleft palate
• diabetes
• heart disease
• hypertension
• inflammatory bowel disease
• mental retardation
• obesity