Wk8 Mendelian Inheritance

Question 1

What are single gene disorders?

Answer 1

Mutations in single genes (often causing loss of function)

Question 2

what are multi factorial diseases?

Answer 2

Variants in genes causing alteration of function (also called common complex disorders)

Question 3

What are chromosome disorders?

Answer 3

Chromosomal imbalance causes alteration in gene dosage

Question 4

What are mitochondrial disorders?

Answer 4

Generally affect organ systems with high energy requirement.

Question 5

What are somatic mutations?

Answer 5

Cause cancer. Inactivation of both alleles (two “hits”) of a gene involved in growth required

Question 6

Dominant types of single gene disorder

Answer 6

Heterozygotes with one copy of the altered gene have the condition

Question 7

Recessive types of single gene disorder

Answer 7

Homozygotes with two copies of the altered gene have the condition

Question 8

X-linked recessive types of single gene disorder

Answer 8

Males with one copy of the altered gene on the X- chromosome have the condition

Question 9

What are autosomal dominant conditions?

Answer 9

• Dominant: describes any trait expressed in a heterozygote
• Variation in expression
• Penetrance
• New mutations
• Anticipation

Question 10

What do mutations cause?

Answer 10

• some mutations can cause gain of function but majority of mutations in autosomal dominant disorders cause loss of function of the allele
• e.g. half the number of LDL receptors on the cell membrane in familial hypercholesterolaemia
• the majority of mutations in autosomal recessive disorders abolish action of the allele

Question 11

Dominant or recessive pattern of inheritance?

Answer 11

Depends on how the cell copes with effectively half the amount of gene produce
Enzyme = no clinical effect (recessive)
Structural protein or receptor = clinical effect (dominant)

Question 12

How to diagnose using DNA?

Answer 12

Is this a normal variant or pathogenic?
• Synonymous/silent SNP?
• Missense mutation?
• Nonsense mutation?
• Frameshift mutation?

Before assuming that a sequence change is the cause of a genetic condition (and not just a polymorphism) determine the likely effect on gene expression or function

Question 13

What are exceptions to mendel’s rules in autosomal dominant inheritance?

Answer 13

Neurofibromatosis type 1
 Autosomal dominant 
 Skin café au lait
patches
 Multiple neurofibroma

Question 14

What are exceptions to mendels rules in autosomal dominant inheritance?

Answer 14

• Variation in expression
• Reduced/incomplete penetrance
• New mutation
• Anticipation
• Mosaicism

Question 15

What does Huntington disease demonstrate?

Answer 15

• age related penetrance

• Autosomal dominant inheritance
• Progressive neurological disorder
– involuntary movements – dementia
– psychiatric disturbance

Question 16

What is age dependent penetrance?

Answer 16

• A delay in the onset of a genetic disease
• Huntington disease
50% of people with the mutation have developed signs by age 50

Question 17

What is myotonic dystrophy?

Answer 17

• Autosomal Dominant
• Muscle weakness
• Impaired muscle contraction after relaxation (myotonia)
• Usual age of onset 20’s-30s
Congenital myotonic dystrophy- severely affected infants with Respiratory problems

Question 18

Why is Huntington disease a triple repeat disease?

Answer 18

 Usual gene 11-34 CAG repeats = 11-34 glutamine residues in protein
 >34 glutamine residues protein aggregates in brain cell causes progressive cell death
 Runs of >34 CAG repeats in HD gene expand further (particularly during male meiosis) causing earlier age of onset in children of men with HD allele - anticipation

Question 19

How to recognise an autosomal recessive disease from a pedigree?

Answer 19

• Can’t follow the disease through the pedigree
• See siblings affected - ‘horizontal transmission’
• Equal incidence of males and females
• May be evidence of consanguinity

Question 20

What is the chance of this pregnancy being affected with CF?

Answer 20

 Mother must be a carrier (probability = 1)
 Chance of new partner being a carrier obtained from frequency of
condition in population = 1/22
 Chance of an affected pregnancy is therefore 1 x 1/22 x 1x4=1/88
 Determine the CFTR mutation in the affected brother
 Offer carrier testing to both parents

Question 21

What is hardy-Weinberg principle?

Carrier rate

Answer 21

2pq =2(1-q)q=2q-2q2

Question 22

HW - equations

Answer 22

P+q = 1

P2 + 2pq + q2 = 1

Question 23

What are the different letters for?

Answer 23

P = dominant allele
Q = recessive allele
P2 = homozygous dominant genotype 
2pq = heterozygous genotype
Q2 = homozygous recessive genotype

Question 24

Why does HW hold true?

Answer 24

• Random mating
• Infinitely large population
• No preferential selection of genotypes
• No new alleles

Question 25

What are available options with a genetic condition?

Answer 25

• Postpone pregnancy
• No further pregnancies
- adoption
• Further pregnancies - accept risk
- prenatal diagnosis if available
- egg donation
- preimplantation diagnosis if availsble

Question 26

Why do some females show X-linked recessive traits?

Answer 26

• Skewed X-inactivation
• Turner syndrome (45,X)
• Homozygous for a recessive trait
e.g. colour blindness
• X;autosome translocations
- X chromosome involved in the
translocation survives preferentially to maintain functional disomy of the autosomal genes

Question 27

What is a key feature of mitochondrial inheritance?

Answer 27

Exclusively’ maternal inheritance egg cells 100,000 mitochondria sperm cells 100 mitochondria
sperm mitochondria actively expelled from fertilized egg