Genetic diseases

Question 1

Simple modes of inheritance (3)

Answer 1

Monogenic

• Autosomal dominant
• Autosomal recessive
• X linked

Question 2

Autosomal dominant inheritance

Answer 2

• 50% risk in offspring
• males and females equally affected
• affected offspring have affected parent
• occurs in every generation

Question 3

AD diseases

Answer 3

Familial hypercholesterolaemia
Huntingtons
Myotonic dystrophy

Question 4

FH

Familial hypercholesterolemia

Answer 4

mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor
People who have one abnormal copy (are heterozygous) of the LDLR gene may develop cardiovascular disease prematurely at the age of 30 to 40.
Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births

Heterozygous FH is normally treated with statins, bile acid sequestrants, or other lipid lowering agents that lower cholesterol levels. New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.

Question 5

HD

Huntingtons

Answer 5

Huntington disease is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition).

Adult-onset Huntington disease, the most common form of this disorder, usually appears in a person’s thirties or forties. Early signs and symptoms can include irritability, depression, small involuntary movements, poor coordination, and trouble learning new information or making decisions. Many people with Huntington disease develop involuntary jerking or twitching movements known as chorea. As the disease progresses, these movements become more pronounced. Affected individuals may have trouble walking, speaking, and swallowing. People with this disorder also experience changes in personality and a decline in thinking and reasoning abilities. Individuals with the adult-onset form of Huntington disease usually live about 15 to 20 years after signs and symptoms begin.

A less common form of Huntington disease known as the juvenile form begins in childhood or adolescence. It also involves movement problems and mental and emotional changes. Additional signs of the juvenile form include slow movements, clumsiness, frequent falling, rigidity, slurred speech, and drooling. School performance declines as thinking and reasoning abilities become impaired. Seizures occur in 30 percent to 50 percent of children with this condition. Juvenile Huntington disease tends to progress more quickly than the adult-onset form; affected individuals usually live 10 to 15 years after signs and symptoms appear.

HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range.[12] The HTT gene is located on the short arm of chromosome 4[12] at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. … CAGCAGCAG …), known as a trinucleotide repeat.[12] CAG is the 3-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region.[23]

Classification of trinucleotide repeats, and resulting disease status, depending on the number of CAG repeats. However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics. This altered form, called mutant huntingtin (mHTT), increases the decay rate of certain types of neurons.

Trinucleotide CAG repeats over 28 are unstable during replication, and this instability increases with the number of repeats present.[12] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.[12] This causes the number of repeats to change in successive generations, such that an unaffected parent with an “intermediate” number of repeats (28–35), or “reduced penetrance” (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.[12] Such increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.[12] Instability is greater in spermatogenesis than oogenesis;[12] maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.[12][26] It is rare for Huntington’s disease to be caused by a new mutation, where neither parent has over 36 CAG repeats

Question 6

Myotonic dystrophy

Answer 6

Myotonic dystrophy is a long term genetic disorder that affects muscle function. Symptoms include gradually worsening muscle loss and weakness. Muscles often contract and are unable to relax. Other symptoms may include cataracts, intellectual disability and heart conduction problems. In men, there may be early balding and an inability to have children.

Myotonic dystrophy is an autosomal dominant disorder which is typically inherited from a person’s parents. There are two main types: type 1 (DM1), due to mutations in the DMPK gene, and type 2 (DM2), due to mutations in the CNBP gene. The disorder generally worsens in each generation. A type of DM1 may be apparent at birth. DM2 is generally milder. They are types of muscular dystrophy. Diagnosis is confirmed by genetic testing.

Myotonic dystrophy affects more than 1 in 8,000 people worldwide. While myotonic dystrophy can occur at any age, onset is typically in the 20s and 30s. It is the most common form of muscular dystrophy that begins in adulthood. It was first described in 1909, with the underlying cause of type 1 determined in 1992.

In DM1, there is an expansion of the cytosine-thymine-guanine (CTG) triplet repeat in the DMPK gene

DM2 is caused by a defect of the CNBP gene on chromosome 3. The specific defect is a repeat of the cytosine-cytosine-thymine-guanosine (CCTG) tetranucleotide in the CNBP gene. As it involves the repeat of four nucleotides, it is not a trinucleotide repeat disorder, but rather a tetranucleotide repeat disorder.

Question 7

Trinucleotide repeat disorders - gain of function

Answer 7

HD
MD
Fragile X

Question 8

Reduced penetrance

Answer 8

Can occur even in AD diseases:

Some people affected less than others

heterozygous but no clinical phenotype

‘skipping’ generations

Question 9

Variable expressivity

Answer 9

individuals show only some of the symptoms

can occur in AD

Question 10

Late onset

Answer 10

disease not apparent until already passed on

can occur in AD

Question 11

Penetrance

Answer 11

Proportion of individuals with the genotype who present with features of the condition
(can occur in AD)

Question 12

Expressivity

Answer 12

Severity expressed by the phenotype
(phenotypic variability)
(can occur in AD)

Question 13

Autosomal recessive inheritance

Answer 13

25% risk in offspring
males and females equally affected
often no family history
mutation may be homozygous or compound homozygous or compound heterozygous

Question 14

Anticipation

Answer 14

as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington’s disease and myotonic dystrophy,

Question 15

compound heterozygote

Answer 15

The presence of two different mutated alleles at a particular gene locus.

Question 16

Autosomal recessive diseases

Answer 16

CF
Hereditary hemochromatosis
PKU

Question 17

Cystic Fibrosis

Answer 17

1/2500
carrier: 1/25
CFTR transmembrane conductor receptor
Cystic fibrosis (CF) is a genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine

Question 18

PKU

Answer 18

1/10,000
PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders
cannot metabolise Phe

Question 19

X linked dominant inheritance

Answer 19

lethal in males so only females affected
male miscarriages
female-female transmission
e.g. RTT, fragile x

Question 20

Rett syndrome

RTT

Answer 20

Rett syndrome is due to a genetic mutation of the MECP2 gene. This gene occurs on the X chromosome Typically it develops as a new mutation, with less than one percent of cases being inherited from a person’s parents. It occurs almost exclusively in girls. Boys who have a similar mutation typically die shortly after birth

a genetic brain disorder which typically becomes apparent after 6 to 18 months of age in females. Symptoms include problems with language, coordination, and repetitive movements. Often there is slower growth, problems walking, and a smaller head size. Complications can include seizures, scoliosis, and sleeping problems. Those affected, however, may be affected to different degrees (reduced penetrance)

Question 21

X linked recessive inheritance

Answer 21

female to male/female transmission (no male-male)
predominantly affects males
carrier females less severely affected (2 X’s)
e.g. haemophilia, duchenne muscular dystrophy

Question 22

Hemizygous

Answer 22

single copy of a gene (e.g. males have 1 X)

Question 23

Fragile X

Answer 23

X linked DOMINANT
FMR1 gene
CGG trinucleotide repeat disorder
mental retardation
DNA methylase methylates on the cpg islands! So protein not expressed. Leads to classic fragile x appearance due to chromatin condensation
Females show reduced penetrance

Question 24

X inactivation

Answer 24

X-inactivation (also called lyonization) is a process by which one of the copies of the X chromosome is inactivated in some female mammals. The inactive X chromosome is silenced by it being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin.