Understanding patterns of

inheritance
This presentation builds on session 1
exploring patterns of inheritance
 Patterns of inheritance
The objectives of this presentation are to:

• Understand how genes are inherited

• Understand the differences between the inheritance patterns
associated with Autosomal dominant, Autosomal recessive, X-
linked recessive and chromosomal abnormalities
• Understand that the environment can impact on some
common complex conditions
So how are genes passed on from parent to
child? Gene

• Genes in the cell nucleus are

physically located on 23 pairs
of chromosomes
• One set of 23 chromosomes is
inherited from each parent Chromosome

• Therefore, of each pair of

genes, one is inherited from a
person’s mother, and one
from their father
Diagram showing just one pair
of the 23 pairs of
chromosomes in the cell
nucleus. The location of one
of the genes on this
chromosome is shown.
 Classification of genetic disorders
Single Gene Disorders

Alterations in single genes

Male

Multifactorial diseases

Variants in genes + environment

Chromosome disorders

Chromosomal imbalance
 Single gene disorders

Some medical conditions are caused by a change

in just one or both copies of a particular pair of
genes. These are called “single gene disorders”.

The three common types of single gene disorders are called:

•Autosomal dominant
•Autosomal recessive
•X-linked
 Dominant
These individuals are called Heterozygotes with one
copy of the altered gene they are affected

Recessive
Homozygotes must have two copies of the altered gene to
be affected

X-linked recessive
Males with an altered gene on the X-
chromosome are always affected
Male
 Autosomal dominant inheritance
Examples of Autosomal Dominant Conditions
• Huntington disease
• Neurofibromatosis type 1
• Marfan syndrome
• Familial hypercholesterolemia
• Familial Adenomatous Polyposis (FAP)
• Prader-willi
Autosomal dominant inheritance

Parents

Gametes

At
conception

Affected Affected Unaffected

 Huntington's disease (HD)

is a neurodegenerative genetic disorder that affects

muscle coordination and leads to cognitive decline
and psychiatric problems.
It typically becomes noticeable in mid-adult life. HD
is the most common genetic cause of abnormal
involuntary writhing movements called chorea,
which is why the disease used to be called
Huntington's chorea.
 Cause
• The disease is caused by
an autosomaldominant mutation in either of
an individual's two copies of
a gene called Huntingtin.
• Expansion of a CAG (cytosine-adenine-
guanine) triplet repeat stretch within
the Huntingtin gene results in a different form
of the protein, which gradually damages cells
in the brain
 Physical symptoms

• Development of tics (involuntary movement) in the

fingers, feet, face, or trunk
• Increased clumsiness
• Loss of coordination and balance
• Slurred speech
• Jaw clenching or teeth grinding
• Difficulty swallowing or eating
• Continual muscular contractions
• Stumbling or falling
 Physical symptoms

• Hostility/irritability
• Lack of energy
• Ongoing disinterest in life (lack of pleasure or
joy)
• Bipolar disorder (manic-depression) in some
Huntington's patients
 Treatment for Huntington's
Disease
The emphasis today is on living positively with
Huntington's Disease. An integrated, multi-
disciplinary approach focuses on the triad of:
• diet and supplements
• exercise
• spiritual and psychosocial support
 Neurofibromatosis type 1 (NF1)
• Neurofibromatosis type 1 (NF1) is a multisystem
genetic disorder that is characterized by cutaneous
findings, most notably café-au-lait spots and axillary
freckling, by skeletal dysplasias, and by the growth of
both benign and malignant nervous system tumors,
most notably benign neurofibromas.
 Cause
• NF-1 is a microdeletion syndrome caused by
a mutation of a gene located on chromosomal
segment 17q11.2 on the long arm
of chromosome 17 which encodes a protein
known as neurofibromin (not to be confused
with the disorder itself) which plays a role
in cell signaling.
• Flat pigmented lesions of the skin called café
au lait spots, are hyper pigmented lesions that
may vary in color from light brown to dark
brown;this is reflected by the name of the
condition, which means "coffee with milk."
 Signs/symptoms
• Congenital musculoskeletal disorders may or may not be
present
• Cutaneous conditions may be observed in early infancy
• Small tumors may arise in the retina which can
eventually lead to blindness
• Learning disabilities may arise in preschool children
 Signs/symptoms
• Neurofibromas may occur and cause many
dependent neurological conditions and
cutaneous and skeletal disfigurement
• Depression and social anxiety may occur as a
result of disabilities caused by the condition
• Neurofibromas may transition into cancer
which can be fatal
 Treatment
• There is no cure for the disorder itself. Instead,
people with neurofibromatosis are followed
by a team of specialists to manage symptoms
or complications.
 Marfan syndrome
• is a genetic disorder of connective tissue. It
has a variable clinical presentation, ranging
from mild to severe systemic disease. The
most serious manifestations involve defects of
the heart valves and aorta, which may lead to
early death if not properly managed.
 Cause
• The syndrome is caused by the misfolding
of fibrillin-1, a glycoprotein which
forms elastic fibers in connective tissue and
contributes to cell signaling activity by binding
to and sequestering transforming growth
factor beta (TGF-β).
 Cause

• The mutated fibrillin binds poorly to TGF-β,

which results in an accumulation of excess
TGF-β in the lungs, heart valves, and aorta.
 S/S
• Disproportionately long, slender limbs with
thin, weak wrists and long fingers and toes.
• Abnormal curvature of the spine,
• Unexplained stretch marks on the skin.
• Partial lens dislocation
• Nearsightedness and blurred vision are
common.
Autosomal dominant inheritance

Marfan syndrome
(a) Arachnodactyly (long fingers). (b ) Dislocated lens.

Fig. 3.2 ©Scion Publishing Ltd

 Treatment
• There is no cure for Marfan syndrome, but life
expectancy has increased significantly over
the last few decades and is now similar to that
of the average person.
• At present (2013), the syndrome is treated by
simply addressing each issue as it arises and,
in particular, preventative medication even for
young children to slow progression of aortic
dilation if such exists.
 Autosomal dominant inheritance
Parents

Gametes
Autosomal dominant inheritance

Parents

Gametes

At
conception

Affected Affected Unaffected

 Autosomal recessive inheritance
Examples of Autosomal recessive conditions
• Sickle Cell disease
• Cystic fibrosis
• Batten Disease
• Congenital deafness
• Phenylketonuria (PKU)
• Spinal muscular atrophy
• Recessive blindness
• Maple syrup urine disease
 Sickle-cell disease
• is a genetically passed down blood disorder,
caused by an abnormality in the oxygen-
carrying protein haemoglobin found in red
blood cells.
• This leads to a propensity for the cells to
assume a rigid, sickle-like shape under certain
circumstances.
 Sickle-cell disease
• Sickle cell disease is associated with a number
of acute and chronic health problems, such as
severe infections, attacks of severe pain
("sickle-cell crisis"), stroke, and a decreased
life expectancy.
 Cause
• Sickle-cell disease occurs when a person
inherits two abnormal copies of the
haemoglobin gene, one from each parent.
Several subtypes exist, depending on the
exact mutation in each haemoglobin gene. A
person with a single abnormal copy does not
experience symptoms and is said to
have sickle-cell trait. Such people are also
referred to as carriers.
 Genetic Cause
• The gene defect is a known mutation of a
single nucleotide (see single-nucleotide
polymorphism - SNP) (A to T) of the β-globin
gene, which results in glutamic acid (E/Glu)
being substituted by valine (V/Val) at position
6.
 s/s
• Sickle cell crisis
• Vaso-occlusive crisis
• Splenic sequestration crisis
• Acute chest syndrome
• Aplastic crisis
• Hemolytic crisis
• Dactylitis
 Treatment
• In 2001 it was reported that sickle-cell disease had
been successfully treated in mice using gene
therapy.
• The researchers used a viral vector to make the
mice—which have essentially the same defect that
causes human sickle cell disease—express
production of fetal hemoglobin (HbF), which an
individual normally ceases to produce shortly after
birth.
 Treatment
• In humans, using hydroxyurea to stimulate
production of HbF has been known to
temporarily alleviate sickle cell disease
symptoms. The researchers demonstrated
that this gene therapy method is a more
permanent way to increase therapeutic HbF
production.
 Treatment
• Phase 1 clinical trials of gene therapy for sickle
cell disease in humans were started in 2014.
The clinical trials will assess the safety and
initial evidence for efficacy of an autologous
transplant of lentiviral vector modified bone
marrow for adults with severe sickle cell
disease.
 Treatment
• As of 2014 however no randomized controlled
trials have been reported.
• Analgesics
• Blood transfusions
• NSAIDs
• Cystic fibrosis (CF) is a genetic disorder that affects
mostly the lungs but also the pancreas, liver, kidneys,
and intestine.
• CF is inherited in an autosomal recessive manner. It is
caused by the presence of mutations in both copies
of the gene for the cystic fibrosis transmembrane
conductance regulator (CFTR) protein.
• Those with a single working copy are carriers and
otherwise mostly normal. CFTR is involved in
production of sweat, digestive fluids, and mucus.
When CFTR is not functional, secretions which are
usually thin instead become thick. The condition is
diagnosed by a sweat test and genetic testing.
Screening of infants at birth takes place in some
areas of the world.
 S/S
• difficulty breathing and coughing up mucus as a
result of frequent lung infections
• sinus infections
• poor growth
• fatty stool
• clubbing of the fingers and toes
• infertility in males, due to congenital absence of vas
deferens
• accumulation of thick, sticky mucus
 Treatment
• There is no cure for cystic fibrosis.Lung
infections are treated with antibiotics which
may be given intravenously, inhaled, or by
mouth. Sometimes the
antibiotic azithromycin is used long term.
Inhaled hypertonic saline andsalbutamol may
also be useful. Lung transplantation may be an
option if lung function continues to worsen.
• Pancreatic enzyme replacement and fat-
soluble vitamin supplementation are
important, especially in the young. While not
well supported by evidence, many people
use airway clearance techniques such as chest
physiotherapy.
Cystic fibrosis
(a) The outlook for cystic fibrosis patients has improved over the years but they still need
frequent hospital admissions, physiotherapy and constant medications. (b) Chest X-ray of
lungs of cystic fibrosis patient. © Erect abdominal film of newborn with meconium ileus
showing multiple fluid levels. Photos (a) and (b) courtesy of Dr Tim David, Royal Manchester
Children’s Hospital.

Fig. 1.2 ©Scion Publishing Ltd

Photos (a) and (b) courtesy of Dr Tim David
 AUTOSOMAL RECESSIVE INHERITANCE

Parents

Parent who are carriers for the same

autosomal recessive condition have one
copy of the usual form of the gene and
one copy of an altered gene of the
particular pair
 AUTOSOMAL RECESSIVE INHERITANCE

Parents

Sperm/Eggs

A parent who is or the altered The other parent who is also a

a carrier passes gene into the eggs carrier for the same condition
on either the or sperm passes on either the usual
usual gene gene or the altered gene into
his/her eggs or sperm
 AUTOSOMAL RECESSIVE INHERITANCE

Parents

Sperm/Eggs

Unaffected Unaffected
Unaffected (carrier) Affected
(carrier)
 X-Linked recessive inheritance
Examples of X-Linked Recessive Conditions
• Fragile X syndrome
• Haemophilia
• Duchenne muscular dystrophy (DMD) (Becker BMD)
• Fabry disease
• Retinitis pigmentosa
• Alport syndrome
• Hunter syndrome
• Ocular albinism
• Adrenoleucodystrophy.
Effects of haemophilia
(a) Bleeding around elbow. (b) A retinal bleed. (c) Repeated bleeds into joints produce severe
arthritis.

Fig. 4.2 ©Scion Publishing Ltd

Photos courtesy of Medical Illustration, Manchester Royal Infirmary (a and c), and Andrew Will (b)
 X-linked recessive inheritance
Male Female
X Y
X X

One copy of an altered gene on An altered copy on one of the X

the X chromosome causes the chromosome pair causes
disease in a male. carrier status in a female.
 X-linked inheritance where the mother is a carrier
Father Mother

Parents
(Unaffected) (Carrier)

Gametes Y X
X X

At
conception

Daughter Daughter (Carrier) Son Son (Affected)

 Polygeneic Inheritance
• Single gene disorders are quite rare
• Single gene disorders either give risk to a
condition or they don’t

• Most traits are Polygenic’ i.e. 1 trait coded by

a number of altered and unaltered genes
working together
 Common Polygenic Disorders
• Alzheimer's
• Diabetes
• Cancer
• Eczema
 Multifactorial inheritance

• Inheritance controlled by many genes plus the

effects of the environment

• Congenital • Adult onset disorders

malformations Diabetes mellitus
Cleft lip/palate Epilepsy
Congenital hip dislocation Glaucoma
Congenital heart defects Hypertension
Neural tube defects Ischaemic heart disease
Manic depression
Pyloric stenosis
Talipes Schizophrenia
The contributions of genetic and environmental factors to human
diseases

Haemophilia Peptic ulcer

Osteogenesis imperfecta Diabetes

Duchenne Club foot

muscular dystrophy Pyloric stenosis Tuberculosis
Dislocation of hip

100% genetic 100%

GENETIC ENVIRONMENTAL
Environmental

Spina bifida Scurvy

Ischaemic heart disease
Phenylketonuria Ankylosing spondylitis
Galactosaemia

Rare Common
Genetics simple Genetics complex
Unifactorial Multifactorial
High recurrence rate Low recurrence rate
Multifactorial
• Examples include some cases of cleft lip
and palate; neural tube defects; diabetes
and hypertension
• Caused by a combination of genetic
predisposition and environmental
influences
• Pattern – more affected people in family
than expected from incidence in
population but doesn’t fit dominant,
recessive or X-linked inheritance patterns
 Chromosomal abnormalities
Some medical conditions are caused abnormalities
in chromosome number or structure.
 Chromosome anomalies
• Cause their effects by altering the amounts of products of the
genes involved.

– Three copies of genes (trisomies)

= 1.5 times normal amount.

– One copy of genes (deletions)

= 0.5 times normal amount.

– Altered amounts may cause anomalies directly or may alter the balance of
genes acting in a pathway.
Most frequent numerical anomalies
in liveborn
Autosomes
Down syndrome (trisomy 21: 47,XX,+21)
Edwards syndrome (trisomy 18: 47,XX,+18)
Patau syndrome (trisomy 13: 47,XX+13)

Sex chromosomes
Turner syndrome 45,X
Klinefelter syndrome 47,XXY

All chromosomes
Triploidy (69 chromosomes)