Inheritance Patterns

Question 1

In pedigree drawings how are males and females identified?

Answer 1

Males are squares

Females are circles

Question 2

How are relationships stated on pedigree drawings?

Answer 2

Partners have a line between them
Siblings have a line above them
Line down for children

Question 3

On pedigree drawings how are genetic diseases shown?

Answer 3

Affected people are shaded

Carriers have dots in

Question 4

What does consanguineous mean?

Answer 4

relating to or denoting people descended from the same ancestor.
“consanguineous marriages may give rise to recessive syndromes”

Question 5

How are consanguineous couples denoted in pedigree drawings?

Answer 5

Double line between the partners

Question 6

Describe autosomal dominant inheritance

Answer 6

Manifest in HETEROZYGOUS form
Multiple generations affected
Both sexes affected
Male to female & female to male transmission
Most will have an affected parent 
50% risk to offspring

Question 7

What are the characteristics of autosomal dominant inheritance?

Answer 7

Most individuals have an affected parent (not everybody due to cases of new mutations or incomplete penetrance)
Males and females are equally likely to inherit allele and be affected
Risk for each child of an affected parent is ½
If an affected individual’s siblings/children are not affected, and they don’t carry the mutation they can’t pass it on to their offspring

Question 8

What is penetrance?

Answer 8

Percentage of individuals who carry the mutation AND develop symptoms of the disorder

Question 9

Where is age dependent penetrance most likely seen?

Answer 9

many dominant disorders show age-dependant penetrance

Question 10

What is variable expressivity?

Answer 10

The variation in severity / symptoms of disorder between individuals with same mutation
E.g. Neurofibromatosis

Question 11

What is meant by mosaicism?

Answer 11

the state of being composed of cells of two genetically different types.

Question 12

Outline the new mutation rate of neurofibromatosis

Answer 12

de novo mutation rate varies considerably between AD conditions

Question 13

Describe the somatic mosaicism seen in neurofibromatosis

Answer 13

new mutation arising at early stage in embryogenesis

Present in only some tissues/cells

Question 14

When does germline mosaicism occur in neurofibromatosis patients?

Answer 14

(gonadal mosaicism): new mutn arises during oogenesis or spermatogenesis
mutn present in variable proportion of gametes; can be transmitted to offspring

Question 15

What can we anticipate about neurofibromatosis?

Answer 15

worsening of disease severity in successive generations

characteristically occurs in triplet repeat disorders

Question 16

Describe autosomal recessive inheritance

Answer 16

Manifest in HOMOZYGOUS/ COMPOUND HETEROZYGOUS form
Carriers (heterozygote) not affected
Both sexes affected
Male to female and female to male transmission
Usually one generation affected
May be consanguinity
e.g. cousin marriages

Question 17

What is compound heterozygosity?

Answer 17

Medical condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state

2 mutns in same gene
Mutns are different

Question 18

Give an example of a compound heterozygous condition

Answer 18

E.g. Cystic fibrosis
∆F508
G542X

Question 19

What is compound homozygosity?

Answer 19

Homozygous mutation is the presence of the identical mutation on both alleles of a specific gene

2 mutns in same gene
Identical mutns

Question 20

Give an example of compound homozygous disease

Answer 20

E.g Cystic fibrosis
∆F508
∆F508
May suggest consanguinity

Question 21

Within families where are autosomal recessive disorders usually seen?

Answer 21

Trait often found in clusters of siblings but not in parents & offspring.

Question 22

What is the recurrence risk of autosomal recessive inheritance?

Answer 22

Recurrence risk = 1/4 for each sibling of affected person

Question 23

What is the carrier probability of autosomal recessive disorders?

Answer 23

Carrier probability =2/3 for unaffected siblings of affected person.
All offspring of affected person are obligate carriers

Question 24

How does X-linked inheritance work within women

Answer 24

Women have two X chromosomes
Two copies of X-linked genes
Can be homozygous or heterozygous

Question 25

Explain how X-linked inheritance works within men

Answer 25

Men have one X and a Y
Only a single copy of X-linked genes
Hemizygous

Question 26

Describe recessive X-linked inheritance

Answer 26

Recessive
Women are carriers + unaffected
No male to male transmission

Question 27

Describe dominant X-linked inheritance

Answer 27

Women are affected

Males more severely affected/lethal

Question 28

What are the rules of x-linked inheritance

Answer 28

X-linked genes never passed from father to son

All daughters of affected males are obligate carriers

Children of carrier females have a 50% chance of inheriting mutant allele

Question 29

What is skewed X-inactivation?

Answer 29

normally the majority of genes on one of a woman’s X-chromosomes are inactivated

generally random but ~10% of women have uneven or skewed X-inactivation

Question 30

What is meant by manifesting carriers?

Answer 30

some women have some symptoms in X-linked recessive conditions e.g. cardiomyopathy in DMD

Question 31

What is Y-linked inheritance?

Answer 31

Always and only passed from fathers to sons

Question 32

What is a mutation?

Answer 32

> a change in the genetic material
A pathogenic mutation (pathogenic variant) results in an alteration of the function of the gene product and can cause a disease phenotype

Question 33

What types of mutations are there?

Answer 33

Substitutions (point mutations)
Deletions
Insertions

Question 34

Where in DNA are mutations found?

Answer 34

Found in:
Coding DNA
Non-coding DNA (such as promoters and introns)

Question 35

What is a silent mutation?

Answer 35

nucleotide change w/o amino acid change: synonymous substitution

Question 36

What is a missense point mutation?

Answer 36

Replacement of a single nucleotide -> forms incorrect amino acid which may produce a malfunctioning protein

Question 37

What are the impacts of amino acid substitution?

Answer 37

Physicochemical similarity between the two amino acids
Functional role of the specific domain of the protein
Phylogenetic conservation of original amino acid amongst diverse species

Question 38

What is a nonsense mutation?

Answer 38

Incorrect sequence causes the shortening of a protein sequence

Question 39

What are the consequences of base insertions and deletions?

Answer 39

For both insertions and deletions:
In-frame (multiple of three)
Frameshift (not a multiple of three)

Question 40

Summarise the classic modes of Mendelian Inheritance

Answer 40

Autosomal dominant
Autosomal recessive
X-linked
Y-linked

Question 41

Within the classic modes of inheritance what other factors can alter gene inheritance?

Answer 41

Pleiotropy, mosaicism, expressivity, penetrance

Question 42

How do we estimate the mode of inheritance?

Answer 42

We estimate a mode of inheritance by examining pedigrees