Patterns of Single-Gene Inheritance

Diseases: 1. Monogenic/Mendelian(caused by one gene: Autosomal dominant, Autosomal recessive, X linked

dominant, X linked recessive) 2. Multifactorial (caused by both genetic anD environmental factors)

Locus - position of a gene on a chromosome.

Alleles - alternative variants of a gene.
Wild-type or common allele or normal allele is the allele that is present in the majority of
individuals.
Variant or mutant allele - is the allele that differs from wild-type and contains a mutation.
Genotype - is the set of alleles that make up persons genetic constitution.
Phenotype - is the observable expression of a genotype as a morphological, clinical, cellular, or
biochemical trait. Phenotype may be either normal or abnormal.
If there are at least two relatively common alleles at the locus in the population, the locus is said to
exhibit polymorphism (literally "many forms"). Frequency: more than 1%
Mutation is a term used in medical genetics to indicate a new genetic change that has not been
previously known in a family or merely to indicate a disease-causing mutant allele.
Frequency:
less than 1%
Homozygote - is a person or a genotype, with a pair of identical alleles at a locus encoded in nuclear
DNA.
Heterozygote - is a person or a genotype, who has different (one normal and one mutant) alleles at a
locus.
Compound heterozygote when two different mutant alleles of the same gene are present.
Hemizygoute when a male has an abnormal allele for a gene located on the X chromosome and
there is no other copy of the gene.
Pedigree - a graphical representation of the family tree, with use of standard symbols.

The patterns shown by single-gene disorders in pedigrees depend chiefly on:

whether the phenotype is dominant (expressed when only one chromosome of a pair carries the
mutant allele and the other chromosome has a wild-type allele at that locus) or
recessive (expressed only when both chromosomes of a pair carry mutant alleles at a locus);
the chromosomal location of the gene locus, which may be on an autosome (chromosomes 1 to 22)
or
on a sex chromosome (chromosomes X and Y).

Autosomal and X-Linked Inheritance

Autosomal disorders affect males and females equally.
For X-linked disorders:
Males have only a single X and are therefore are hemizygous with respect to X-linked genes (46,XY
males are never heterozygous for alleles at X-linked loci, whereas females can be heterozygous or
homozygous at X-linked loci).
In females, alleles for most X-linked genes are expressed only from one of the two X chromosomes
(X-inactivation).
Dominant and Recessive Inheritance
Recessive Inheritance
A phenotype expressed only in homozygotes and not in heterozygotes.
Most of the recessive disorders are due to mutations that reduce or eliminate the function of the
gene product, so-called loss-of-function mutations.
Heterozygotes, with only one functioning allele, can typically make sufficient product (50%),
thereby preventing disease.
Dominant Inheritance
The phenotype expressed in both homozygotes and heterozygotes.
In a pure dominant disease, homozygotes and heterozygotes for the mutant allele are both affected
equally.
Usually, dominant disorders are more severe in homozygotes than in heterozygotes, in which case
the disease is called incompletely dominant.
Sometimes, two different alleles for a locus are expressed simultaneousely, in this case the two
alleles are termed codominant (Ex: AB blood groups).

FACTORS AFFECTING PEDIGREE PATTERNS:

Penetrance & Expressivity
Penetrance is the probability that a gene will have any phenotypic expression at all. Penetrance is an
all-or-none concept.
In other terms, penetrance is the percentage of people with a predisposing genotype who are
actually affected.
When some of those who have the appropriate genotype completely fail to express the trait the gene
is said to show reduced penetrance.
Expressivity is the severity/degree of expression of the phenotype among individuals with the same
disease-causing genotype.
When the severity of disease differs in people who have the same genotype, the phenotype is said to
have variable expressivity.
Even in the same family, two individuals carrying the same mutant genes may have some signs and
symptoms in common, whereas their other disease manifestations may be quite different.
Ex: Neurofibromatosis 1 (NF1)
NF1 is a common disorder of the nervous system, the eye, and the skin that occurs in approximately
1 in 3500 births.
NF1 is characterized by growth of multiple benign tumors, neurofibromas, in the skin; presence of
multiple pigmented skin lesions known as caf au lait spots; growth of small benign tumors called
Lisch nodules on the iris of the eye; and less frequently, mental retardation, central nervous system
tumors, and the development of cancer of the nervous system or muscle.
Thus, the condition has a pleiotropic phenotype.
Adult heterozygotes almost always demonstrate some sign of the disease (penetrance is therefore
100%), the severity of the disease may be different - variable expressivity.

CORRELATING GENOTYPE AND PHENOTYPE

When a genetic disorder that appears to be inherited as a single-gene disorder is thoroughly analyzed, it is
frequently found that certain similar phenotypes are actually determined by different genotypes.
Genetic heterogeneity is a phenomenon in which a single phenotype (or trait or genetic disorder)
may be caused by different mutations.
Pleiotropy when a single gene may cause multiple phenotypic expressions or disorders.

Genetic heterogeneity can be classified as either "allelic" or "locus".

Allelic heterogeneity means that different mutations within a locus cause the same phenotypic
expression = different alleles of a gene cause the same disease/symptoms.
Ex: there are over 1400 known mutant alleles of the CFTR gene that cause cystic fibrosis (CF).
Locus heterogeneity means that genes in completely different/unrelated loci cause a single disorder.
Ex: Retinitis pigmentosa has autosomal dominant, autosomal recessive, and X-linked origins.
However, only one mutant locus is needed for the phenotype to manifest.
Characteristics of Autosomal Dominant Inheritance
The phenotype usually appears in every generation, each affected person having an affected parent
(vertical transmission).
Males and females are equally likely to transmit the phenotype, to children of either sex.
Any child of an affected parent has a 50% risk of inheriting the trait.
A significant proportion of isolated cases are due to new mutation.
An isolated case may also be due to reduced penetrance.

Incompletely Dominant Inheritance:

Ex: Achondroplasia is a well known, incompletely dominant skeletal disorder of short-limbed
dwarfism with normal intelligence and large head. Marriages between two achondroplastic
individuals are not uncommon. A homozygous child of two heterozygote is affected severely and
causes death soon after birth.
Ex: Familial hypercholesterolemia is an autosomal dominant disorder leading to premature coronary
heart disease. In this disorder, the rare homozygous patients have a more severe disease, with an
earlier age at onset and much shorter life expectancy, than do the relatively more common
heterozygotes.
New Mutation in Autosomal Dominant Inheritance
Most dominant conditions of medical importance come not only through transmission of the mutant
allele from a heterozygous parent to the offspring, but through a spontaneous, new mutation.

This is because dominant disorders can occur when only one of the pair of alleles at a locus is
defective, whether it is inherited from a heterozygous parent or arises through a new, spontaneous
mutation.

Characteristics of Autosomal Recessive Inheritance

Males and females are equally likely to be affected.
Parents of an affected child are asymptomatic carriers of mutant alleles.
An autosomal recessive phenotype typically is seen only in the sibship of the proband, not in parents,
offspring, or other relatives (horizontal transmission).
The parents of the affected person may in some cases be consanguineous/relatives.
The recurrence risk for each sib of the proband is 1 in 4.

Sex-Influenced Disorders:
Some autosomal recessive phenotypes are sex-influenced, that is, expressed in both sexes but with
different frequencies or severity.
Ex: hemochromatosis is disorder of iron metabolism when dietary iron absorption is increased and
results in excessive body stores of iron (in heart, liver, and pancreas).
Disease incidence is lower in females because of lower dietary intake of iron, lower alcohol usage,
and increased iron loss through menstruation among females.
Consanguinity mating of relatives:
Mutant alleles of autosomal recessive traits can be handed down in families for numerous
generations without ever appearing in the homozygous state and causing disease.
The chance that both parents are carriers of a mutant allele at the same locus is increased if the
parents are related and could each have inherited the mutant allele from a single common ancestor.
Consanguinity is a union of individuals related to each other closer than second cousins.
Rare Recessive Disorders in Genetic Isolates:
Some rare genetic disorders appear more frequently in certain populations.
Ex: Tay-Sachs disease is a neurological disorder that affects children from 6 months of age. Affected
children become blind and regress mentally and physically and causes death at the age of 3-4 years.

Tay-Sachs disease has an increased frequency in Ashkenazi Jews in North America, where Tay-Sachs
disease is 100 times more frequent than in other population (carrier frequency is 1 in 30). Because
these people seldom mate with the representatives of other populations, the probability of two
unrelated carriers to meet and produce an affected child is greatly increased!

X-linked Inheritance
X and Y chromosomes differ greatly (size & gene content)!
Y 70 genes, mostly involved in the formation of male hormones & male reproductive system.
X 1500 genes, mostly associated with disease phenotypes (not involved in sex determination).
Because males have one X chromosome but females have two, there are only two possible genotypes in
males and three in females (with respect to a mutant X-linked allele).

Genotypes
Males

Hemizygous X
Hemizygous X

Females

Phenotypes
Unaffected

Affected

Homozygous X /X
H

Unaffected

Heterozygous X /X

Unaffected (usually)

Homozygous X /X

Affected

X-inactivation & dosage compensation

X inactivation is a normal physiological process in which one X chromosome is inactivated in somatic

cells in females.
Inactive X is seen as Barr body.
It equalizes the expression of most X-linked genes in the two sexes.
Thus, females have two cell populations: one in which X is a active and the other with inactive X.
Thus, two females heterozygous for an X-linked disease may have very different clinical
manifestation, because they differ in the proportion of cells that have the mutant allele on the active
X chromosome in a relevant tissue.

Characteristics of X-linked Recessive Inheritance

The incidence of the trait is much higher in males than in females.
Heterozygous females are usually unaffected ( but some may express the condition with variable
severity as determined by the pattern of X inactivation).
The mutant allele is never transmitted directly from father to son, but it is transmitted by an affected
male to all his daughters.
A significant proportion of isolated cases are due to new mutation.
Ex: Hemohpilia A
Disorder in which the blood fails to clot normally because of a deficiency of protein clotting factor
VIII.

It is typically expressed phenotypically in all males it but only in those females who are homozygous
for the mutation.
Also known as royal hemophilia, because of its occurrence Britains Queen Victoria descendants,
who was a carrier herself.

Pedigree pattern demonstrating an X-linked recessive disorder such as hemophilia A, transmitted from an
affected male through females to an affected grandson and great-grandson.

Xh represents the mutant factor VIII allele causing hemophilia A, and XH represents the normal allele.
If a hemophiliac mates with a normal female, all the sons receive their father's Y chromosome and a
maternal X and are unaffected
But all the daughters receive the paternal X chromosome with its hemophilia allele and are carriers.

AFFECTED MALE BY NORMAL FEMALE: X /Y X /X

h

X /X

X /X

Daughters: all carriers

X /Y

X /Y

Sons: all unaffected

NORMAL MALE BY CARRIER FEMALE: X /Y X /X

H

X /X

X /X

Daughters: normal, carriers

X /Y

X /Y

Sons: normal, affected

H
H

H
h

An gene for an X-linked disorder is occasionally present in both a father and a carrier mother,
and female offspring can then be homozygous affected.
Shown is the pedigree
of common X-linked
disordercolor blindness.

Most X-linked diseases are so rare, however, that it is unusual for a female to be
homozygous unless her parents are consanguineous.
AFFECTED MALE BY CARRIER FEMALE: X /Y X /X
h

X /X

X /X

Daughters: 1/2 carriers, 1/2 affected

X /Y

X /Y

Sons: 1/2 normal, affected

H
H

h
h

Characteristics of X-linked Dominant Inheritance

Affected males with normal mates have all affected daughters and all normal sons.
Both male and female offspring of female carriers have a 50% risk of inheriting the phenotype.
Vertical transmission on the pedigree
Affected females are twice as common as affected males, but affected females typically have milder
(although variable) expression of the phenotype.
Ex: Hypophosphatemic (vitamin D-resistant) rickets
Mutation impairs the absorption of filtered phosphate by the kidney tubules
Although both sexes are affected, the serum phosphate level is less depressed and the rickets less
severe in heterozygous females than in affected males.