6- Inheritance Patterns

Question 1

define penetrance

Answer 1

percentage of individuals who carry the mutation and develop the symptoms of the disorder

Question 2

define incomplete penetrance

Answer 2

reduced chance of developing associated symptoms of the disorder despite having the mutation

Question 3

define variable expressivity

Answer 3

variation in the severity and presentation of symptoms among individuals with the same genetic mutation

Question 4

define de novo mutation

Answer 4

changes in the gene sequence not inherited from parents ; spontaneous mutation that occurs in cells

what autosomal dominant disorders rely on to exist

Question 5

autosomal dominance

Answer 5

genetic disorders involving a dominant gene on an autosomal chromosome

disease manifest in heterozygous form. relies on spontaneous de novo mutations to exist - disease tends to be so severe the affected person dies before they can reproduce

transmission across multiple generations between males and females. offspring of an affected person have a 50% risk of getting the disease

features:
- incomplete penetrance
- variable expressivity = same genetic mutation may lead to different clinical presentations in different people
- de novo mutation rate varies depending on severity of disorder
- mosaicism = affected individual has a mix of cells with and without the mutation
- anticipation

Question 6

define mosaicism

Answer 6

presence of a mutation in only a proportion of cells in an individual

Question 7

define anticipation associated with diseases

Answer 7

a worsening of disease severity and an earlier age of onset in successive generations

seen in some autosomal dominant disorders - especially those caused by trinucleotide expansions (e.g. Huntington’s)

Question 8

autosomal recessive

Answer 8

genetic disorders involving recessive genes on autosomal chromosomes

homozygous or compound homozygous - can suggest consanguinity

carriers are unaffected individuals each carrying one mutated alleles - transmit this allele to their offspring. male and female carriers possible

appear in one affected generation. affected individuals born from unaffected carrier parents.

features:
- traits found in clusters of siblings but not necessarily between parents and offspring
- recurrence risk for each sibling of an affected individual is 25%
- carrier probability for unaffected siblings of an affected person is 2 in 3
- offspring of an affected person are all obligate carriers = will carry the mutated allele

Question 9

define compound homozygous

Answer 9

having different mutations on each allele = cause the same functional impairment

Question 10

define homozygous

Answer 10

same mutation on both alleles

Question 11

X-linked inheritance - name the two types

Answer 11

involves genes located on the X-chromosome

two types:
- X-linked recessive inheritance
- X-linked dominant inheritance

Question 12

X-linked recessive inheritance

Answer 12

females are carriers in they inherit one mutated, one normal X allele = unaffected

males that inherit a mutated X allele are affected = lack the second X chromosome to compensate

no male-to-male transmission
e.g. haemophilia, colour blindness

features:
X-linked genes don’t pass from father to son, all daughters of affected males are obligate carriers
sons of carrier females have a 50% chance of inheriting the mutated allele
skewed X-inactivation = may exhibit symptoms of X-linked recessive disease in females with skewed X-inactivation

Question 13

X-linked dominant inheritance

Answer 13

females who inherit one mutated X allele are affected

males who inherited one mutated X allele = more severely affected

e.g. intellectual disability

Question 14

define skewed X-inactivation

Answer 14

occurs in females with two XX chromosomes

one of the X chromosomes is preferentially inactivated = leads to to a disproportionate expression of genes from one of the X chromosomes

this event is skewed as X chromosome inactivation shouldn’t be preferential – it should

Question 15

Y-linked inheritance

Answer 15

involves genes located on the Y chromosome

traits always passed from father to son
e.g. types of male infertility

Question 16

define a mutation

Answer 16

a change in genetic material - can be found in coding and non-coding DNA, which defines its impact

Question 17

define a synonymous missense mutation

Answer 17

a base change that doesn’t change the amino acid for a protein

Question 18

define a non-synonymous missense mutation

Answer 18

base change causes a change in amino acid

• can cause a premature stop codon = truncated protein that doesn’t function well
• tend to be degraded my nonsense-mediated decay pathway

Question 19

list types of mutations

Answer 19

substitutions, deletions, insertions
synonymous and non-synonymous missense mutations

Question 20

describe how insertion deletions can shift the reading frame

Answer 20

affect the reading frame in two ways:

1. in-frame mutation = insertion is a multiple of 3, less likely to cause disease as the additional amino acid won’t mess up the entire protein sequence
2. frameshift mutation = insertion isn’t a multiple of 3. shifts entire reading frame for a completely different series of amino acids, can cause disease/damage

Question 21

factors that affect the impact of an amino acid base substitution

Answer 21

1. functional role of a specific domain of a protein = if the functional part of the protein is affected by the amino acid variant it can lead to problems
2. physiochemical similarity between the two amino acids = hydrophilic to hydrophobic, single or double ring structure
   - more significant differences are more likely to cause biological problems
3. phylogenetic conservation of original aa amongst diverse species
   = more conserved – most likely important