DLA 12 Gene

Question 1

Define polymorphism

Answer 1

Multiple forms (alleles) of a gene in population (>1% of population); note that Polymorphisms are common, so a polymorphism is unlinkely to be causative of a disorder

Question 2

Describe what a mutation (pathogenic variant)

Answer 2

Change in base sequence of the gene which results in clinical expression (phenotype). Most pathogenic variants are relatively rare in the population

Question 3

Differentiate between locus and allele

Answer 3

Locus= location of a gene

Allele= one of the alternative forms of a gen3 that occur at a locus

Question 4

What is a recurrence risk?

Answer 4

Probability that the offspring of a couple will express the genetic disorder. For single gene disorder, it doesn’t depend on the number of previously affected/unaffected offspring. Depends on mode of inheritance of a disorder

Question 5

What is a pedigree?

Answer 5

The genogram or diagrammatic representation of the family history
-Comes from the French “foot of the crane (a bird foot)

Question 6

What is a consultand?

Answer 6

The person who approaches a physician or geneticist for a consultation

• this person may or may not be affected
• Consultand could be a parent of a child with a disorder

Question 7

What is a proband?

Answer 7

The affected individual in the family who gains the attention of the physician due to a genetic condition

Question 8

Briefly summarize autosomal dominant disorders

Answer 8

• Affected children receive the disease-causing allele from an unaffected parent
• Skipped generations NOT common (vertical inheritance)
• Males and females are typically affected with equal frequency
  - Male to male (father to son) transmission is seen

Question 9

Explain recurrence risk for autosomal recessive inheritance

Answer 9

Each conception is an independent event

If both parents are carriers then:
-25% risk for the disorder with each conception if both parents are carriers

• 50% risk for each conception that the child will be a carrier
• 25% chance that the child will inherit both functional alleles

Question 10

Explain the reasoning behind the 2/3 rule?

Answer 10

In autosomal recessive sib ships (brothers and sisters) what proportion of the Non-affected sibs would be carriers?

Is sib is not affected , that sib may not be ‘aa’ because he/she is not affected

Therefore, there are only three other genotypes available:

• AA
• Aa
• aa

Notice that two out of the three are carriers:

So for AR disorders, 2/3 of healthy sibs of a known affected person are carriers

Caveat: disorder is highly penetrant and observable early in life

Question 11

Explain how the risk that a person is a carrier for an allele controlling autosomal recessive traits/disorders

Answer 11

The parents of an aff3cted individual are carriers

• The unaffected sibs of an affected individual are at a 2/3 risk of being carriers (this is the 2/3 rule)
  
  • Their children would therefore be at 1/3 risk of being carriers, because they have a 1/2 risk of passing the allele to the next generation
• The offspring of an affected individual and a non-carrier must be carriers
• Children of a carrier and a non-carrier are at a 50% risk of being carriers
• Children of a person at 1/2 risk would then have a 1/4 risk of being carriers

Question 12

Explain: homozigosity by descent: consanguity increases the risk that an autosomal recessive disorder will be uncovered

Answer 12

• In children born from consanguineous marriages, an allele from a common ancestor may become homozygous
• All humans are carriers of some recessive mutations that if homozygous would result in severe disease or lethality
• In this pedigree, all individuals have been genotypes for the disease associated locus (A)
• The affected individual in the 4th generation is homozygous for the allele that originated in the great grandmother

Question 13

What are the main mechanisms for AD inheritance?

Answer 13

1. Haploinsufficiency
2. Gain of function
3. Dominant negative
4. Loss of heterozygosity
   
   • idea is that inheritance of one disease allele in the germline occurs (from the gamete), and then loss of the second, functional copy occurs, either during fetal development, or following birth sometime during the lifetime of the individual. We give only one example in this section (NF1), but will develop it in much more detail during the Cancer genetics section if the course

Question 14

Explain familial hypercholesterolemia (LDL receptor deficiency ) as an example of ha0loinsufficiency

Answer 14

• The LDL receptor is found on the hepatocyte (liver cell)
• LDL receptor binds to LDL particles to clear them from the blood
• People who are heterozygous for a loss of function mutation in one LDLR allele have 2x the level of circulating LDL, and high circulating cholesterol
• Xanthomas May form. Yellowish deposition of cholesterol near elbows, ankles, wrists, palpebral areas

Question 15

How does FHC/

DLR deficiency exhibit allelic heterogeneity ?

Answer 15

An example of autosomal dominance is due to haploinsufficiency

Almost an infinite number of different mutation alleles in LDLR May destroy the function of a gene -this is the definition of alleilic heterogeneity

LDLR pathogenic variants may exhibit a high degree of allelic heterogeneity
-thousands of different LDLR pathogenic variants are known, each one is a different allele

Question 16

How can FHC be an example of locus heterogeneity?

Answer 16

Hypercholesterolemia can be caused by variants in Mendelian fashion

So a person could have FHC and have two functional copies of the LDLR gene

• Meaning the FHC in this family is not caused by LDLR haploinsufficiency
• So the FHC in this person is caused by mutation somewhere else

This is an example of locus heterogeneity

Question 17

Describe briefly what usually happens for haploinsufficiency in enzymes

Answer 17

Only a little bit of enzyme should be needed to satisfy needs of the cell and person to remain disease free

So in most cases, a person who is heterozygous for a loss of function mutation in just about ANY enzyme wouldn’t have a phenotype (no disease)

-Acute intermittent porphyria is an exception

Question 18

What is acute intermittent porphyria?

Answer 18

A lot of heme is needed by the heme

Heme is needed in :

1. Red blood cells
2. Any cell with mitichondria
3. Liver cells for cytochrome p450 detoxification enzymes

Since there is no demand on the pathway, both alleles must be functional

Question 19

What are the symptoms of acute intermittent porphyria?

Answer 19

Intermittent symptoms of anxiety, nausea, pain, constipation, diarrhea

• Often develops and changes over time
• Several other genes involved in porphyrin ring synthesis also have AD associated disorders

Question 20

What are the types of gain of funcyom mutations?

Answer 20

1. Mutation causes the gene to do more than what is normally does (can be due to more protein proteins acts in an unregulated manner, some. Other mechanisms)
2. Mutation causes a “new” function- this is the attainment of novel function
   - can be due to a variety of functions

Question 21

Describe achondroplasia as a gain of function mutation.

Answer 21

A specific DNA base pair change causes the encoded protein to function in an unregulated manner

FGFR3 gene encodes a receptor protein tyrosine kinase

Normally FGFR3 protein signals to bone growth plates during development to begin ossification

-If FGFR3 signals in an unregulated manner, premature ossification of bone growth plates occurs, and person develops disproportionate short stature

Question 22

Is there a lot of allelic heterogeneity with respect to achondroplasia?

Answer 22

No, only a very specific mutation will cause FGFR3 protein to become unregulated

About 99% of all individuals with achondroplasia all have the same pathogenic variant

• Leads to the glycine 380 Arginine amino acid substitution (Gly380Arg)
• Meaning the mutation causes Gly at position 380 of the protein to be Arg (no need to memorize this exact mutation, it is just used as an example because it is so specific ; if used as a subject of an exam question, these details will be given)

Question 23

Explain Huntington disease as an “attainment of a novel function”

Answer 23

Huntington disease is caused by an expansion of an unstable triplet of bases in an exon of the Huntingtin gene (HTT)

The codons in the exons are expanded to glutamine amino acids in the coded protein (polyglutamine tract expansion)

Causes new functions of the gene (unknown), that leads to death if neurons

Question 24

Explain the anticipation of Huntington

Answer 24

As the repeat expands, it tends to (but not always) become more stable

• So as the trait is passed down generations, the repeat length might increase (longer polyglutamine tracts)
• Correlated with earlier onset if the disorder-called anticipation

Question 25

What are the two types of causes of Marfan syndrome ?

Answer 25

2 types of FBN1 mutations may cause Marfan syndrome

1. Mutations that lead to less fibrillin-1 protein- so this would be a FBN1 loss of function gene, and the AD inheritance would be explained by haploinsufficiency
2. A mutation that allow the fibrillin protein to be made in normal amounts, but what is made will interact inappropriately with the normally formed fibrillin-1 (from the other allele ) and also other connective tissue proteins (dominant negative )

Question 26

What is the cause of OI (brittle bone disease)?

Answer 26

OI caused by collagen defects

• Caused by mutation of COL1A1 or COL1A2
• The inheritance pattern of OI is similar to MARFAN syndrome: OI can be explained either by haploinsufficiency or dominant negative methods of autosomal dominance
• similar rational used for Marfan disease

Question 27

Compadre dominant negative with haploinsufficiency

Answer 27

When considering Marfan syndrome or OI, the disorder is most likely more severe when caused by the dominant negative variant

Question 28

What causes Neurofibromatosis?

Answer 28

By inheritance of one pathogenic NF1 allele from a gamete

• About 1/2 cases are inherited from an affected parent
• Approximately 1/2 cases are caused by de-novo mutation occurring during gametogenesis gametogenesis (so the parent is not affected )

-So, in most of the cells in the fetus —> person still have one functional NF1 allele

After fertilization, a second mutation may cause the loss of the remaining functional NF1 allele in a somatic cell (cell in the body), leading to a cell that now has no functional NF1 protein

• It is almost guaranteed that this will happen in a person(usually many times)
• So cells will form that have no functional NF1; these grow into the tumors
• For this reason, NF1 has very high penetrance
• However! Signs and symptoms may be highly variable among different individuals, even within the same family

Question 29

Summarize the function of NF1

Answer 29

The NF1 suppresses cellular proliferation, loss of NF1 leads to benign tumors (neurkfibromas) and increased risk of other cancer types

Question 30

What are the symptoms of neurofibromas?

Answer 30

Cafe au lait spots

Lisch nodules of the eye

Usually no cancerous (benign) tumors that are often located on or just under the skin

Question 31

What is the cause and treatment of galactosemia?

Answer 31

Caused by homozygous loss of function in one of 3 different enzymes responsible for metabolism of galactose

• Lactose (milk sugar) is a dimer of glucose and galactose
• Treatment for galactosemia is a restriction of milk

Question 32

What causes phenylketonuria ?

Answer 32

Inheritance of 2 loss of function alleles of the enzyme of the enzyme phenylalanine hydroxylase (PAH gene)

• Build up of Phe is toxic, causes irreversible brain damage
• Newborn screening, USA, Canada, UK, Europe, most developed countries

Question 33

What us the treatment for phenylketonuria?

Answer 33

Inability to convert phenylalanine to tyrosine

Treatment: dietary restriction of phenylalanine

Question 34

What is homocystinuria?

Answer 34

• Individuals affected with homocystinuria May develop a body shape resembling Marfan syndrome
• The high levels circulating homocysteine interact with connective tissue and also cause neurological manifestations
• Autosomal recessive
• Inborn error of metabolism
• Autosomal recessive- the parents of an affected individuals are themselves carriers (typically) and are NOT affected

Question 35

How is ADA deficiency leading to SCID?

Answer 35

Autosomal recessive SCID due to ADA deficiency (purine degradation pathway)

If ADA is deficient, the build up of dATP is toxic to B-cell and T-cell development= severe combined immunodeficiency

ADA= adenosine deaminase

Question 36

What is the sickle cell disease cause?

Answer 36

Caused by a mutation in the gene for beta-globin

• Causes a Glu6val change in the encoded protein
• Causes hemoglobin to polymerize

This is GAIN OF FUNCTION

-The Hb that has the SCD variant can still bind and release oxygen

Question 37

Explain sickle cell trait

Answer 37

The person with sickle trait is at risk of having a sickle crisis when an extreme conditions

• Such as combined high altitude + vigorous exercise
• So if one knows how to look, or looks carefully enough(with the correct test), a phenotype can sometimes be uncovered in the otherwise “unaffected heterozygote “ person

Question 38

What is a terminology SCD and SCD Trait?

Answer 38

SCD is considered autosomal recessive because for a person to have sickle cell disease, both alleles of the gene encoding beta-globin must have the mutation

• When a person has sickle cell trait, we can say that the alleles are displaying co-dominance because both can be detected by protein electrophoresis
• We can “see” both forms of the protein with the laboratory test
• Both forms of the protein are equally expressed

Question 39

Explain pseudoautosomal dominance

Answer 39

An autosomal recessive condition present in individuals in two or more generations of a family, thereby appearing to follow a dominant inheritance pattern

An affected parent may have an affected child
-appears to be vertical transmission

Question 40

What are the common explanations of pseudo-autosomal dominance?

Answer 40

1. High carrier frequency of the disorder
   - Sickle cell disease in Sub-Saharan areas of Africa
2. Higher incidence of consanguity
3. Increased carrier frequency because of small population
   • geographical, social or religious isolation

Question 41

When a carrier (Aa) and an affected (aa) mate then 1/2 the offspring will be affected. The other half will be carriers. What is this called?

Answer 41

Called pseudo-dominance because it is easy to mistakenly interpret as dominant trait from a simple pedigree (the 1/2 disease transmission risk would Suggest dominance at first glance)

Question 42

What is it mean to be pseudo-dominant?

Answer 42

Appearent autosomal dominant inheritance when a heterozygote & homozygote for an autosomal recessive disorder have affected children

Question 43

What are the factors that can increase incidence of autosomal recessive trait in a family, group, or population?

Answer 43

-Consanguity

• Heterozygote advantage
  
  1. Sickle cell disease
  2. CF
  3. Hemochromatosis

Genetic isolation

• Geographic, such as outports in Newfoundland
• Religous, such as Amish, Hutterites etc.
• Cultural (language), such as Asian populations in UK

Assortative mating
-People associate and marry with “like” (e.g. Hearing or visually impaired individuals)

Question 44

Explain blood types as an example of codominance

Answer 44

• The addition of the sugar is accomplished by specific enzymes
• Enzymes produced by the A and B alleles add a different terminal sugar (O is a null)
• In AB heterozygotes, both sugars are present on cell surface at equivalent level

Question 45

What is incomplete dominance?

Answer 45

Phenotype is intermediate between the parents

Phenotype is intermediate between the two dominant alleles

• Father has curly hair
• Mother has straight hair
• Baby has wavy hair

Red and white flower= pink flower