Autosomal Recessive Inheritance (AR)

1.Introduction
Recessive genes can only be expressed in homozygous
(aa) individuals. There are more heterozygous (Aa)
carriers than homozygous (aa) who actually express the
trait. All three genotypes (AA, aa, Aa) are possible
throughout any population.
2. The four criteria for identifying recessive genes:
1) The first appearance of the recessive trait within a
family usually is in the children of the unaffected
parents.
2) 25% of the children will be express trait.
3) Both males and females can express the trait unless
it is a recessive sex linked gene.
4) Ratio of disease in consanguineous marriage is
higher than non-consanguineous marriage.
 Autosomal Recessive Inheritance

There is horizontal inheritance (normal

parents often have more than one affected
child).
Affected individuals usually have unaffected
partners and all their children will be
carriers.

New mutation is almost never a

consideration.
 3.Recurrence risk calculation

A consanguineous marriage is said to be

the union between two people, genetically
related, by descent from a common
ancestor.
• Relatives may be categorized according to
their  genetic "closeness" to the patient:
•
First-degree relatives include the patient's
mother, father, siblings, and children .
(Probability of same gene is 1/2)
Second-degree relatives include
grandparents, aunts, uncles, nieces,
nephews, and grandchildren (1/4)
Third-degree relatives include first cousins
(1/8)
consanguineous marriages showed
significantly higher rates of still births,
infant mortality and congenital
malformations.
Oculocutaneous albinism type 1 (OCA1) is
characterized by reduced synthesis of melanin in the
skin, hair, and eyes, associated with ocular findings of
nystagmus, reduced iris pigment with iris translucency,
reduced retinal pigment, foveal hypoplasia with
significantly reduced visual acuity, and misrouting of
the optic nerves resulting in alternating strabismus and
reduced stereoscopic vision.
Albinism Why? High risk

panmixis consanguineous
?

?
• Pop frequency of albinism=1/10000.
• Carrier frequency ≈1/50
1/50 ×1/50 × 1/4=1/10000; 1/50 × 1/8 × 1/4=1/1600
Tay-Sachs disease, the prototype hexosaminidase
A deficiency, is characterized by loss of motor
skills beginning between three and six months of
age with progressive evidence of
neurodegeneration, including seizures, blindness,
and eventual total incapacitation and death,
usually before age four years.
 sickle-cell anemia
Sickle cell anemia is the most common
inherited blood disorder in the United States,
affecting about 72,000 Americans or 1 in 500
African Americans. SCA is characterized by
episodes of pain, chronic hemolytic anemia
and severe infections, usually beginning in
early childhood.

SCA is an autosomal recessive disease

caused by a point mutation in the
hemoglobin beta gene (HBB) found on
chromosome 11p15.4. About 8% of the
African American population are carriers.
A mutation in HBB results in the
production of a structurally
abnormal hemoglobin (Hb),
called HbS. Hb is an oxygen
carrying protein that gives red
blood cells (RBC) their
characteristic color. Under
certain conditions, like low
oxygen levels or high hemoglobin
concentrations, in individuals who
are homozygous for HbS, the
abnormal HbS clusters together,
distorting the RBCs into sickled
shapes. These deformed and rigid
RBCs become trapped within
small blood vessels and block
them, producing pain and
eventually damaging organs.
 Phenylketonuria ( PKU )
A common genetic disorder (1 out of 12,000
births) which results from a deficient
enzyme required for the metabolism of the
amino acid phenylalanine .
Failure to recognize the disorder early in life
results in mental retardation . Many states
require all newborns to be screened for this
disease.
The only treatment for PKU is
to avoid eating foods that
contain phenylalanine. Babies
are put on a special formula
that does not contain
phenylalanine.
 SEX-LINKED INHERITANCE
In humans, the term sex-linked traits usually refers
to X-linked traits and Y-linked traits.

1. The human X-chromosome is much larger than

the Y. Thus, there are more X-linked than Y-
linked traits.
2. Most X-linked genes have no homologous loci on
the Y chromosome.
3. Most genes on the Y chromosome not only have no
X counterparts, but they encode traits found only
in males (e.g. testis- determining factor).
X-linked recessive inheritance
disease ， XR

X-linked dominant inheritance

disease ， XD
 X-linked recessive inheritance disease ， XR

• Genotype and Phenotype

XAXA XAXa XaXa XAY XaY

Marriage types of different genotypes

XAXa × XAY XAXA × Xa Y

XA Xa XA Y XA Xa Y

XA Y Xa Y XA XA XA Xa XA Xa XA Y
 Colorblind
• Causes and Risks:

• Colorblindness is an inherited condition that

is sex linked recessive. As a result, very few
women are colorblind but approximately 1 in
10 men has some degree of colorblindness.

• The most common form of colorblindness is

red-green and has a wide range of variability
within this group from very mild to extreme.
Hemizygous = A condition where only one copy of a
gene is present in a diploid organism, refers
especially to X-linked genes in the male but also
applies to genes on any chromosome segment that is
deleted on the homologous chromosome.
Hemophilia A is a hereditary blood disorder,
primarily affecting males, characterized by a
deficiency of the blood clotting protein known as
Factor VIII that results in abnormal bleeding.
Babylonian Jews first described hemophilia more
than 1700 years ago; the disease first drew
widespread public attention when Queen Victoria
transmitted it to several European royal families.
England's Queen Victoria was a carrier for this
disease. The allele was passed to three of her
daughters and one son.
X-linked
recessive
inheritance

1) More affected males than affected females. Affected males

transmit the gene to all daughters, but not to any of their
sons.
2) Affected females must have an affected father and, at
least, a carrier mother ; Affected males are hemizygous.
3) The daughters of an affected male will usually be a carrier
(heterozygote) and thus not show the trait.
4) Half of the sons of carrier females are affected.
Since royal
families in Europe
commonly
intermarried, the
allele spread, and
may have
contributed to the
downfall of the
Russian monarchy
(Czar Nicholas' son
Alexei suffered
from hemophilia A
inherited from his
mother who carried
Victoria's genetic
secret).
Mutation of the HEMA gene on the X
chromosome causes Hemophilia A.

The HEMA gene codes for Factor VIII, which is

synthesized mainly in the liver, and is one of
many factors involved in blood coagulation; its
loss alone is enough to cause Hemophilia A even
if all the other coagulation factors are still
present.
Duchenne muscular dystrophy (DMD)
One of a group of muscular dystrophies characterized
by the enlargement of muscles. DMD is one of the most
prevalent types of muscular dystrophy and is
characterized by rapid progression of muscle
degeneration that occurs early in life. All are X-linked
and affect mainly males an estimated 1 in 3500 boys
worldwide.
 Gowers’ Pseudohyper
-trophy of
sign calf muscles

Electromyo-
Awkward graphy
Lumbar
manner of
hyperlordosis & Muscle
walking
biopsy

Signs and symptoms

 Congestive heart failure or arrhythmia  Respiratory disorders

 Abnormal heart muscle  Higher risk of neurobehavioral

(Cardiomyopathy) disorders
 The gene for DMD, found on the X chromosome, encodes
a large protein dystrophin. Dystrophin is required inside
muscle cells for structural support; Without it, the cell
membrane becomes permeable, so that extracellular
components enter the cell, increasing the internal pressure
until the muscle cell "explodes" and dies. The subsequent
immune response can add to the damage.

 2.5Mb(0.08% of the
human genome), one of
the longest human genes
known
Xp21.1-p21.2  Dystrophin is a 427-kDa
intracellular protein,
found in skeletal, smooth
and cardiac muscle
 High rate and various
forms of mutation:
deletion, duplication,
point mutation and
complex forms with more
than two types of
mutaion
pseudohypertrophic muscular dystrophy , DMD
(MIM 310200)Xp21-p21.3

I 1 2

II 1 2 3 4 5 6 7

III 1 2 3 4 5 6 7 8 9
 Inheritance pattern
X-recessive inheritance , XR

Genetic characteristics

 Males are primarily affected. Rarely, females XAXa

may have symptoms, but carrier females are
usually unaffected.

 A son of a carrier mother has a 50% risk to

inherit the mutation.
XAXa XaY XAXa
 Cross transmission.
 Affected males transmit the mutation to all
daughters.

X aY XaY Xa Y
Medical management & Genetic counselling

Braces Make
Standing definitive
frames diagnosis
Cardiac care wheelchairs Prenatal
Respiratory care diagnosis
Spinal curvatures &
Moderately exercise Privacy
Usually did Advices for
not survive protection
beyond teen High risk family:
years Avoid pregnancy
& life &
expectancy PGD
is increasing (preimplantation
genetic diagnosis ）
X-linked dominant inheritance
disease ， XD

Anti-vitamine D ricket

hypophosphatemic (or vitamin

D resistant) rickets,
characterized by low blood and
high urinary phosphate, short
stature, and bony deformities.
 X-linked dominant inheritance disease ， XD
1. Among parents of patient, there must be one with disease .
2. Among offsprings of affected males ， daughters are
affected ， sons are normal. Affected males transmit the trait
to all their daughters
3. Among offsprings of affected females ， half of daughters
or sons are affected. Affected females transmit to half of their
children.
4. For rare phenotypes,
affected females are about
twice as common as affected
males, but affected females
typically have milder
expression of the phenotype.
 Criss-cross inheritance
Fathers pass X-linked alleles to only and all of
their daughters.
1. Males receive their X chromosome only from their
mothers.
2. Fathers cannot, therefore, pass X-linked traits to their
sons.

Mothers can pass sex-linked alleles to both sons

and daughters.
1. Females receive two X-chromosomes, one from each
parent.
2. Mothers pass on one X-chromosome (either the maternal
or paternal homologue) to every daughter and son.
 Y-Linked Inheritance

• A small number of genes have been

mapped to the Y chromosome.
• Genes on the Y chromosome pass from
father to sons only; no daughters of
affected males can inherit the gene.
The Y chromosome contains genes associated with

sperm maturation - some cases of infertility are due

to Y-linked genes (the DAZ gene) , azoosperm
 male determination
 hairs in ear channel
hairs in
ear
channel
Genetic Heterogeneity

The majority of inherited human diseases

exhibit genetic heterogeneity. Genetic
heterogeneity means that different mutations
can cause an identical or similar phenotype.
Genetic heterogeneity may be the result of
different mutations at the same locus (allelic
heterogeneity ), mutations at different loci
(locus heterogeneity), or both.
Cystic fibrosis(CF,MIM#219700)
is predominantly a disease of
northern Europeans, caused by
mutations in the CFTR gene.The
live birth incidence of CF ranges
from 1 in 313 among the
Hutterites of southern Alberta,
Canada, to 1 in 90,000 among
the Asian poputation of Hawaii.
Among all U.S. whites, the
incidence is 1 in 3200. the
frequency of carriers for one of
the hundreds of possible mutant
CFTR alleles can be calculated to
be approximately 1/29.
 Allelic Heterogeneity
As one
example,
nearly 1400
different
mutations
have been
found
worldwide in
the cystic
fibrosis
transmembran
e conductance
regulator
(CFTR) among
patients with
cystic fibrosis.
Consanguinity is not the most common explanation for
an autosomal recessive trait. The mating of unrelated
persons, each of whom happens by chance to be a
carrier, accounts for most cases of autosomal recessive
disease, particularly if a recessive trait has a high
frequency in the population. Thus, most affected
persons with relatively common disorder, such as CF,
are not the result of consanguinity, because the mutant
allele is so common in the general population. However,
consanguinity is more frequently found in the
background of patients with rare conditions.
Locus Heterogeneity

For example, retinitis pigmentosa, a common cause

of visual impairment due to photoreceptor
degeneration, has long been known to occur in
autosomal dominant, autosomal recessive, and X-
linked forms.
There are at least 43 loci responsible for 5 X-linked
forms, 14 autosomal dominant forms, and 24
autosomal recessive forms.
Homework:
Match the pedigree with the most likely mode of
inheritance and write down the genotypes of the
proband and his/her parents.