Mendelian Inheritance of Human Disease

Question 1

Describe the basic structural hierarchy of a chromosome

Answer 1

• Chromosome = linear DNA molecule
• Gene = length of DNA which encodes a particular protein
• Genes are arranged along Ch in a linear order-each has a precise position = locus
• Alternative forms of a gene = allele
• Each Ch bears only a single allele at a given locus

Question 2

Describe the basic numerical structure fo human chromosomes

Answer 2

• Human = 46 chromosomes = 2 X 23 homologous pairs
• In females = 2x22 pairs and XX
• In males = 2x22 pairs and XY
• One member of each pair comes from the father, the other from the mother
• Member of each pair has same genes in the same order, but at at any one locus they may have either:
the same genetic variants (alleles) = homozygous or different alleles = heterozygous

Question 3

What is a genetic disease and give some examples of the causes

Answer 3

One caused by a change in the genes
Chromosome aneuploidies (extra or missing chromosome) More subtle chromosome abnormality
Extra piece of chromosome Missing piece of chromosome Change in gene sequence:
Insertion or deletion of a few bases Change of a single base where it matters

Question 4

Describe the potential effects of mutations in promoter and splice site sequences

Answer 4

Stop transcription or cause abnormal splicing

Question 5

Describe the potential effects of mutations in a base change causing an amino acid change

Answer 5

Change in protein sequence
Not every base change causes disease
This may or may not reduce protein function
Some missense mutations make a protein work faster

Question 6

What mutation may cut a genetic sequence short?

Answer 6

Base change causing a premature stop codon

Question 7

Describe the potential effects of mutations in insertion or deletion of bases

Answer 7

remember that 3bp encode 1 amino acid Mutations may be “in-frame” or “out of frame”

Question 8

Describe the potential effects of mutations in trinucleotide repeat expansions

Answer 8

replication of a trinucleotide

Question 9

Go over some mutations and their effects at different parts of the gene

Answer 9

Promotor and splice site sequence changes: Stop transcription or cause abnormal splicing
Base change causing an amino acid change:
Change in protein sequence
Not every base change causes disease
This may or may not reduce protein function
Some missense mutations make a protein work faster
Base change causing a premature stop codon
Insertion or deletion of bases:
remember that 3bp encode 1 amino acid Mutations may be “in-frame” or “out of frame”
Trinucleotide repeat expansions: replication of a trinucleotide

Question 10

Use “The cat sat on the mat” to describe different types of DNA mutation

Answer 10

• The cat sat on the mat
Wild Type

• The cat
Stop

• The car sat on the mat
Missense

• The cat spa to nth ema t
Insertion

• The cas ato nt hem at
Deletion (out of frame)

• The cat on the mat
Deletion (in frame)

• The cat cat sat on the mat
Triplet Expansion

Question 11

What are disorders with mendelian inheritance?

Answer 11

A change in a single gene, sufficient to cause clinical disease, is inherited in a fashion predicted by Mendel’s laws

Question 12

What is non-mendelian inheritance?

Answer 12

Everything else not inherited in a fashion predicted by Mendel’s laws, including common “multifactorial” diseases.

Question 13

What are the different kinds of mendelian inheritance?

Answer 13

Autosomal dominant Autosomal recessive
X-linked
(Mitochondrial)

Question 14

What is the symbol for male in pedigree drawing?

Answer 14

a square

Question 15

What is the symbol for female in pedigree drawing?

Answer 15

a circle

Question 16

What is the symbol for an unaffected individual in pedigree drawing?

Answer 16

a blank shape

Question 17

What is the symbol for an affected individual in pedigree drawing?

Answer 17

a filled in black shape

Question 18

What is the symbol for a miscarriage in pedigree drawing?

Answer 18

a triangle

Question 19

What is the symbol for a dead individual in pedigree drawing?

Answer 19

a diagonal line through the shape

Question 20

What percentage of genes are shared between first degree relatives? (Siblings/Parent/Child)

Answer 20

50% in all cases except for identical twins that share 100% of genes

Question 21

What percentage of genes are shared between second degree relatives?
(Grandparent/Grandchild/Niece/Aunt/half-sibling)

Answer 21

25% in all cases

Question 22

What percentage of genes are shared between third degree relatives? (1st Cousins)

Answer 22

12.5%

Question 23

What is an autosomal chromosome?

Answer 23

Any chromosome that is not a sex linked chromosome

Question 24

Who will inherit an autosomal dominant disease?

Answer 24

Any offspring that carry a copy of the gene for the disease

Disease seen in all generations
50% risk of affected child if parent is affected Disease severity can be variable
(individuals with a mutation may not show disease) Males and females equally likely to be affected

Question 25

Give an example of an autosomal dominant disease

Answer 25

Mutations in Fibrillin 1 (FBN1): Marfan’s Syndrome

> 1300 Identified mutations

25% arise from new mutations, 75% inherited in AD pattern

1 in 5000

Question 26

What is allelic heterogeneity?

Answer 26

When different mutations in the same gene can cause the same disease

Question 27

What is hereditary haemorrhagic telangiectasia type 1 (HHT1)?

Answer 27

A rare autosomal dominant disease that causes abnormal blood vessel formation in skin and mucous membranes, prominently around the lips*.
Often associated with vascular abnormalities of the lungs and the brains as well as nosebleeds from a young age, a more serious form of HHT

Question 28

What is hereditary haemorrhagic telangiectasia type 2 (HHT2)?

Answer 28

A rare autosomal dominant disease that causes abnormal blood vessel formation in skin and mucous membranes, prominently on the tongue*.
Vascular abnormalities of the liver, on the other hand, occur more often in HHT type 2

Question 29

What is locus heterogeneity?

Answer 29

The same disease might be caused by mutations in one of several genes (locus heterogeneity)

Question 30

What must you know when performing a gene test, which pedigree charts may help with?

Answer 30

To do a gene test you need to know approximately where to look

Question 31

What causes sickle cell anaemia on a genetic level?

Answer 31

An alanine nucleotide being replaced with a thymine nucleotide which causes an change in a glutamate to form valine in its place

Question 32

Who will inherit an autosomal recessive disease?

Answer 32

Only those offspring that inherit copies of the disease on both copies of a chromosome will be effected by the full form of the disease. Some with one copy will not be affected by the disease at all but may still pass it on

Often only one generation affected
1 in 4 risk of an affected child if parents carriers Increased likelihood in consanguineous families

Question 33

Why is X linked inheritance important?

Answer 33

In terms of disease genes, the Y chromosome is almost irrelevant

Question 34

What are two famous X linked recessive diseases?

Answer 34

Dystrophin Haemophillia

Question 35

Who will inherit an X linked recessive disease carried by the mother?

Answer 35

Any male offspring who’s X chromosome carries the disease, and no females unless the father also suffers from this disease in which case:
50% of female offspring will inherit the disease with a carrier mother
100% of female and male offspring will inherit it from a mother suffering from the full form of the disease

Question 36

What are the signs of Duchenne Muscular Dystrophy?

Answer 36

Henry
• Mostly effects boys, female carriers may show mild symptoms
• Mild developmental delay
• Slow to walk
• Difficulty standing
• Unable to run
• On examination:
– Hypertrophy of calf muscles 
– Proximal muscle weakness

• Creatine Kinase 10,000iu
In muscular biopsy there is far greater interstitial space and a number of prominent black dots*

Question 37

What do we mean by “Henry” when discussing Duchenne Muscular Dystrophy?

Answer 37

“Henry Standing Up”

A particular way people who suffer from the disease stand up, going to all fours with a level back which is raised upright last

Question 38

Who will inherit an X linked recessive disease carried by the father?

Answer 38

• If an affected male has children
– All of their male children will be normal (no male to male transmission)
– All of their female children will be carriers

Question 39

What are some complications to basic pedigree patterns?

Answer 39

• Nonpenetrance = failure of a genotype to manifest
• Variable Expression= different family members may show different features of a disorder
• Both seen more often in dominant conditions
• Due to influence of other genes and environment, as well as chance

Question 40

Other than chromosomes, where do you keep DNA?

Answer 40

In Mitochondrial DNA

Question 41

Describe mitochondrial DNA

Answer 41

• 16,559 base pairs
• Many copies (because of many mitochondria) in a cell
• Contains important genes for mitochondrial metabolic pathways and ribosomal RNAs
• Inherited almost exclusively maternally
• Point mutations and deletionsoccur

Question 42

Describe mitochondrial inheritance of disease

Answer 42

Rare
Maternal transmission only
Sons and daughters equally affected