lecture notes of KEY GENETIC DISEASES.pdf

Key genetic disorders and syndromes
PHA1003 – Molecular Biology and Genetics
Sr. Instr. Mustafa Çavuşoğlu
mustafa.cavusoglu@baucyprus.edu.tr

• Genes are the building blocks of heredity.
• They are passed from parent to child. They hold the instructions for making proteins.
• Proteins do most of the work in cells. They move molecules from one place to another, build
structures, break down toxins, and do many other maintenance jobs.
• The mutation changes the gene's instructions for making a protein, so the protein does not work
properly or is missing entirely. This can cause a medical condition called a genetic disorder.
• You can inherit a gene mutation from one or both parents. A mutation can also happen during your
lifetime.
Introduction

• There are three types of genetic disorders:
• Single-gene disorders (monogenic) - where a mutation affects one gene. Sickle cell anaemia
is an example.
• Chromosomal disorders - where chromosomes (or parts of chromosomes) are missing or
changed. Chromosomes are the structures that hold our genes. Down syndrome is a
chromosomal disorder.
• Complex disorders (multifactorial) - where there are mutations in two or more genes. Often
your lifestyle and environment also play a role. Colon cancer is an example.
Introduction

• Common genetic disorders
• Chromosomal Disorders;
• Down Syndrome
• Fragile X Syndrome
• Complex Disorders;
• Autism Spectrum Disorder
• Cancer
• Single Gene Disorders;
• Cystic Fibrosis
• Sickle Cell Disease
Introduction

• Down syndrome is a genetic condition where a
person is born with an extra copy of chromosome
21.
• This means that they have a total of 47
chromosomes instead of 46.
• This extra copy changes how the baby’s body and
brain develop, which can cause both mental and
physical challenges for the baby.
Down Syndrome (Chromosomal Disorders)

Down Syndrome
• Half of our chromosomes come from
mother and half come from father.
• Through a process
called meiosis each of your parents
creates a sex cell that contains half
of their chromosomes

• What happens with Down syndrome?
• During both mitosis and meiosis, there is a phase where each chromosome pair in a cell is
separated, so that each new cell can get a copy of every chromosome.
• However, sometimes during this process, a pair of chromosomes doesn’t separate evenly,
which results in one of the new cells having an extra section of chromosome. This is
called nondisjunction.
• With Down syndrome, various types of uneven chromosome separation result in a person
having an extra copy (or partial copy) of chromosome 21.
Down Syndrome

• There are three main types of Down syndrome:
• Trisomy 21
• Mosaicism
• Translocation
Down Syndrome

• Trisomy 21;
• Most common form of Down syndrome, accounting for
about 95% of cases.
• This type of Down syndrome is caused by uneven
separation of chromosome 21 during the creation of sex
cells, which leads to a fertilized egg with three copies of
chromosome 21 instead of two.
• When the fertilized egg is developed, it passes along
the extra copy of chromosome 21 to every cell in the
body
Down Syndrome

• Mosaicism;
• Mosaic means mixture or combination.
• The mosaic form of Down syndrome is much less common,
accounting for about 1-2% of cases.
• In this form, the uneven separation of chromosome 21
happens shortly after an egg has been fertilized.
• Because it leads to a person having some cells with the
typical 46 chromosomes, and some cells with 47 (these
cells have an extra copy of chromosome 21).
• Because only some cells have the extra chromosome,
mosaic Down syndrome may have less prominent
symptoms than trisomy 21.
Down Syndrome

• Translocation;
• In the remaining 4% of cases of Down syndrome, the extra
genetic material is passed on to new cells in a slightly different
way.
• Rather than failing to separate, translocation occurs when a
portion of chromosome 21 breaks off during the replication
process, and then attaches to another chromosome.
• So rather than getting a full extra chromosome, translocation
results in cells with the typical 46 chromosome, plus a little extra
chromosome 21.
• The genes contained in the extra portion of chromosome 21 can
cause many of the symptoms of Down syndrome
Down Syndrome

• Fragile X syndrome (FXS) is an inherited genetic disorder that causes physical abnormalities,
behavioural issues and a wide range of other health problems.
• It's the most common form of inherited intellectual and developmental disability (IDD).
• It gets its name because when you look at the X chromosome through a microscope, part of it looks
“broken” or “fragile.” Another name for the condition is Martin-Bell syndrome.
• Usually, males are more severely affected by this disorder than females.
Fragile X Syndrome (Chromosomal Disorders)

• About one-third of individuals with fragile X syndrome have
features of autism spectrum disorder that affect
communication and social interaction.
• Most males and about half of females with fragile X
syndrome have characteristic physical features that
become more apparent with age. These features include a
long and narrow face, large ears, a prominent jaw and
forehead, unusually flexible fingers, flat feet and in males,
enlarged testicles (macroorchidism) after puberty.
Fragile X Syndrome

• What causes Fragile X Syndrome?
• Mutations in the FMR1 gene cause fragile X syndrome.
• The FMR1 gene provides instructions for making a protein
called FMRP. This protein helps regulate the production of
other proteins and plays a role in the development of
synapses which are specialized connections between nerve
cells.
• Synapses are critical for relaying nerve impulses.
• Nearly all cases of fragile X syndrome are caused by a
mutation in which a DNA segment, known as the CGG triplet
repeat, is expanded within the FMR1 gene.
• Normally, this DNA segment is repeated from 5 to about 40
times. In people with fragile X syndrome, however, the CGG
segment is repeated more than 200 times.
Fragile X Syndrome

• The abnormally expanded CGG segment turns off (silences) the FMR1 gene, which prevents the
gene from producing FMRP.
• Loss or a shortage (deficiency) of this protein disrupts nervous system functions and leads to the
signs and symptoms of fragile X syndrome.
Fragile X Syndrome

• Autism spectrum disorder (ASD) is a neurodevelopmental condition
typically diagnosed during childhood.
• ASD is a developmental disability caused by differences in child’s
brain.
• People with ASD may behave, interact and learn in ways that are
different from other people.
• They may have trouble with social interactions and with interpreting
and using nonverbal and verbal communication.
• There’s no cure for autism, but the symptoms may lessen over time.
Autism Spectrum Disorder (ASD) (Complex
Disorders)

• Autism definition
• Autism means child may have:
• Difficulties interacting with other people or differences in how they interact with others.
• Trouble using and understanding nonverbal communication, like eye contact, gestures and
facial expressions.
• Delayed or absent language development.
• Trouble forming and understanding relationships
Autism Spectrum Disorder (ASD)

• What causes autism?
• There’s no clear-cut cause of ASD. Research supports genetic and environmental factors as some
causes of autism. Scientists believe there could be many different causes of ASD that act together to
change the ways people develop.
• Genetics do play a role in autism. These cases include specific genetic syndromes associated with ASD,
such as fragile X syndrome, and rare changes in genetic code.
• It has been reported that up to 40% of cases of ASD in children have a genetic cause (eg, genetic
syndromes such as fragile X syndrome, Rett syndrome, tuberous sclerosis, mutations in the phosphatase
and tensin homolog [PTEN] gene, and structural chromosomal deletions or duplications that can be
detected using chromosomal microarrays).

• Germline mutations in PTEN, the gene that encodes phosphatase and tensin homolog, have
been identified in up to 20% of children with autism spectrum disorder (ASD) and macrocephaly and
are associated with marked abnormalities in the white matter of the brain.
• Although ASDs are known to be extremely heritable, their common genetic causes remain largely
elusive because of the complex behavioural phenotypes and multigenic etiology of these disorders.

• Cancer is a disease in which some of the body’s cells grow
uncontrollably and spread to other parts of the body.
• Cancer can start almost anywhere in the human body, which is made
up of trillions of cells.
• Normally, human cells grow and multiply (through a process
called cell division) to form new cells as the body needs them.
• When cells grow old or become damaged, they die, and new cells take
their place.
• Sometimes this orderly process breaks down, and abnormal or
damaged cells grow and multiply when they shouldn’t. These cells
may form tumors, which are lumps of tissue. Tumors can be
cancerous or not cancerous (benign).
Cancer (Complex Disorders)

• Cancerous tumors spread into, or invade, nearby tissues and can travel to distant places in the
body to form new tumors (a process called metastasis).
• Cancerous tumors may also be called malignant tumors. Many cancers form solid tumors, but
cancers of the blood, such as leukemias, generally do not.
• Cancer is a genetic disease—that is, it is caused by changes to genes that control the way our cells
function, especially how they grow and divide.
Cancer

• Genetic changes that cause cancer can happen because:
• of errors that occur as cells divide.
• of damage to DNA caused by harmful substances in the environment, such as the
chemicals in tobacco smoke and ultraviolet rays from the sun.
• they were inherited from our parents.
• The body normally eliminates cells with damaged DNA before they turn cancerous. But
the body’s ability to do so goes down as we age. This is part of the reason why there is a
higher risk of cancer later in life.
Cancer

lecture notes of KEY GENETIC DISEASES.pdf

• Cystic fibrosis (CF) is a genetic (inherited) disease that causes sticky, thick
mucus to build up in organs, including the lungs and the pancreas.
• In people who have CF, thick mucus clogs the airways and makes it difficult to
breathe.
• Management includes ways of clearing lungs and a nutrition plan
• Many people think of CF as a lung disease because it affects your lungs and
airways, which can make it hard to breathe and cause frequent infections. But
it’s called cystic fibrosis because it also causes cysts and scarring (fibrosis) in
your pancreas.
• This damage, plus the thick mucus, can block ducts that release
digestive enzymes, making it hard to get nutrients from your digestive tract.
• CF can also affect your liver, sinuses, intestines and sex organs.
Cystic Fibrosis (Single Gene Disorders)

• In people with CF, a change in a gene (genetic mutation) leads to low levels of certain proteins, or proteins
that don’t work properly.
• Because of these faulty proteins, minerals that move water into your mucus (which thins it out) get trapped
inside cells, leaving the mucus thick and sticky.
• People with cystic fibrosis are born with it. It’s a lifelong illness that gets more severe over time
• Types of cystic fibrosis
• There are two types of cystic fibrosis:
• Classic cystic fibrosis often affects multiple organs. It’s usually diagnosed in the first few years of
your life.
• Atypical cystic fibrosis is a milder form of the disease. It may only affect one organ or symptoms
may come and go. It’s usually diagnosed in older children or adults.
Cystic Fibrosis

• What causes cystic fibrosis?
• Changes to the CFTR gene (cystic fibrosis transmembrane conductance regulator) —
called variants or mutations — cause cystic fibrosis. CFTR makes a protein that works
as an ion channel on the surface of a cell. Ion channels are like gates in a cell’s
membrane that allow certain molecules to pass through.
• CFTR usually makes a gate for chloride ions, a type of mineral with a negative electrical
charge. Chloride moves out of the cell, taking water with it, which thins out mucus and
makes it more slippery.
• In people with CF, gene mutations in CFTR prevent this from happening, so the mucus
stays sticky and thick
• There are different categories (classes I to VI) of gene mutation in CFTR that depend on
the effect they have. Some produce no proteins at all, some produce only small
amounts of proteins, and some produce proteins that don’t work properly.
Cystic Fibrosis

• Sickle cell disease (SCD) is the most common inherited blood disorder that affects your red blood cells.
• In SCD, a protein called hemoglobin, located within red blood cells, is abnormal. Hemoglobin is important. It’s
the molecule that carries oxygen in your blood and throughout your body.
• Normal red blood cells are round and flexible. This allows them to move easily through small blood vessels
(capillaries) in your body to deliver oxygen to your organs and tissues.
• In SCD, there’s an abnormal form of hemoglobin called hemoglobin S. This changes the shape of the red
blood cell to a crescent shape and causes red blood cells to become rigid, lack flexibility and stick together.
• This can block blood flow, preventing oxygen from getting to the vital organs and tissues throughout body.
• It can lead to serious complications including pain, infections, and organ damage and failure.
• Additionally, sickle-shaped cells don’t last as long as normal-shaped red blood cells, causing a constant
shortage of red blood cells and leading to anemia. Sickle cell disease is a lifelong condition. But there are
treatment options that can reduce your symptoms and prolong your life.
•
Sickle Cell Disease (Single Gene Disorders)

• What causes sickle cell disease?
• A genetic mutation in the HBB gene causes sickle cell disease.
The HBB gene is responsible for making a part of the hemoglobin.
People with SCD received two mutated HBB genes coded for
abnormal hemoglobin — one from each parent.
• People inherit SCD in an autosomal recessive manner. This means
each parent of a child with SCD carries one copy of the mutated
gene, but they typically don’t show signs and symptoms of the
condition.
Sickle Cell Disease

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