Inheritance Patterns

Question 1

Categories of Genetic Disorders

Answer 1

• Chromosome abnormalities

• Single gene disorders

• Multi-factorial and polygenic disorders e.g. spina bifida, cleft lip and palate

Question 2

Mendel Deduced the Underlying Principles of Genetics

Answer 2

1. Segregation
2. Dominance
3. Independent assortment

Question 3

Dominance

Answer 3

Every gene has 2 alleles that code for a trait

In heterozygotes, one allele is dominant meaning it will always show, one is recessive and is masked by the dominant allele

Question 4

Segregation

Answer 4

Allele pairs separate/segregate randomly from each other during meiosis – each cell has a single allele for each trait

Question 5

Independent Assortment

Answer 5

Traits are transmitted to offspring independently of one another

Question 6

Mendelian Inheritance

Answer 6

• Autosomal and sex-linked
• Dominant and recessive

Question 7

Non-Mendelian Inheritance

Answer 7

• Imprinting
• Mitochondrial inheritance
• Multifactorial
• (Mosaicism)

Question 8

Autosome

Answer 8

Any chromosome, other than the sex chromosomes (X or Y), that occurs in pairs in diploid cells

Question 9

Recessive

Answer 9

Manifest only in homozygotes

Question 10

Allele

Answer 10

One or more alternative forms of a gene at a given location (locus)

normal allele is also referred to as wild type

disease allele carries the pathogenic mutation

Question 11

Homozygous

Answer 11

Presence of identical alleles at a given locus

homozygotes are affected

Question 12

Heterozygous

Answer 12

Presence of two different alleles at a given locus

Heterozygotes are unaffected and are usually referred to as carriers

Question 13

Allelic heterogeneity

Answer 13

The situation where different mutations within the same gene result in the same clinical condition e.g. cystic fibrosis.
Thus an individual with an autosomal recessive condition may be a compound heterozygote for two different mutations

Question 14

In autosomal recessive inheritance the disease manifest in the homozygous state I.e “double-dose” of affected alleles.

Typical features include

Answer 14

Male and females affected in equal proportions

Affected individuals only in a single generation

Parents can be related, i.e. consanguineous

Question 15

Consanguinity

Answer 15

Reproductive union between two relatives.

Question 16

Autozygosity

Answer 16

Homozygosity by descent, i.e. inheritance of the same altered allele through two branches of the same family.

Question 17

Summary (ARI)

Answer 17

Double-dose of same altered gene required to cause problems

· Carrier parents have no health problems themselves, but have 1 in 4 offspring risk

· Healthy siblings have a 2 in 3 chance of being carriers themselves

· AR conditions can affect any family, but more common in consanguineous unions

· Some AR conditions are more common in certain ethnic groups

Question 18

Autosomal Dominant Inheritance

Disease manifest in the heterozygous state, i.e. only one affected gene needed

Typical features include

Answer 18

Male and females affected in equal proportions

Affected individuals in multiple generations

Transmission by individuals of both sexes, to both sexes

sometimes both parents are unaffected, this can be for three reasons: most commonly they don’t have the genes for it, gonadal mosaicism or SOMETIMES the mother has REDUCED PENETRANCE or VARIABLE EXPRESSION i.e. disease is there but not expressed clearly.

Only one defective gene needed. 50% chance of offspring having condition (1 affected and 1 unaffected parent). Example. Huntington’s disease. ONLY WAY TO PASS ON DISEASE FROM MALE TO MALE. Thus if you see male-male transmission, MUST BE AUTOSOMAL DOMINANCE INHERITANCE

Penetrance & variability

Question 19

Penetrance

Answer 19

The percentage of individuals with a specific genotype showing the expected phenotype

• Complete: gene or genes for the trait are expressed in all the population

• Incomplete: the genetic trait is only expressed in parts of the population

Question 20

Expressivity

Answer 20

Refers to the range of phenotypes expressed by a specific genotype

I.e will the disease be expressed more harshly in certain people, will the disease affect at a certain age

Question 21

Recurrence risk

Answer 21

50% for transmission of mutation

BUT will the person be affected?

Depends on penetrance and expression

Question 22

New mutation

Answer 22

Example – Neurofibromatosis type 1, up to 50% of cases occur as result of de novo mutation

Question 23

Anticipation

Answer 23

Whereby genetic disorder affects successive generations earlier or more severely, usually due to expansion of unstable triplet repeat sequences

Example – Myotonic Dystrophy

Question 24

Somatic Mosaicism

Answer 24

Genetic fault present in only some tissues in body.

Question 25

Gonadal (germline) Mosaicism

Answer 25

Genetic fault present in gonadal tissue (reproductive tissue)

-Does not affect the individual with the Germline mosaicism health

Question 26

Late-onset

Answer 26

Condition not manifest at birth (congenital), classically adult-onset

Example – Hypertrophic Cardiomyopathy

Question 27

Sex-limited

Answer 27

Condition inherited in AD pattern that seems to affect one sex more than another

Example – BRCA1/2

Question 28

Predictive testing

Answer 28

Testing for a condition in a pre-symptomatic individual to predict their chance of developing condition

Question 29

Summary (ADI)

Answer 29

Disease manifest in the heterozygous state, i.e. only one affected gene needed

· Male and females affected in equal proportions

• Affected individuals in multiple generations

• Transmission by individuals of both sexes, to both sexes

• Only MOI with male-to-male transmission

• penetrance, variability

Question 30

X-linked Inheritance
Genes carried on X chromosome
Caused by a mutation in genes on the X-chromosome

Typical features

Answer 30

Usually only males affected

Transmitted (usually) through unaffected females

No male-to-male transmission

Eg; haemophilia and duchenne muscular dystrophy

• X-linked can never be passed from father to son (NO MALE-TO-MALE TRANSMISSION - BECAUSE SONS ALWAYS GET THEIR X CHROMOSOME FROM THEIR MOTHER) - all sons from affected male and unaffected female are unaffected

• All daughters from an affected male are CARRIERS all sons are UNAFFECTED

• Males can NEVER be carriers

• Usually only males are affected

• Transmitted (usually) through unaffected females

• X-linked dominant example is Alport’s syndrome (kidneys)

• X-linked recessive example is Duchenne’s muscular dystrophy

Question 31

Lyonization (X inactivation)

Answer 31

Generally only one of two X chromosomes active in each female cell. Can be skewed

As baby girls are developing one of the X chromosomes are switched off- 50% of the genes inherited from mother switched off and 50% inherited from father switched off

• LYONISATION: The process of X chromosome inactivation

• One of the two X chromosomes in every cell in a female is randomly inactivated early in embryonic development.

• X chromosome inactivated to prevent female cels having twice as many gene products from the X chromosome as males

• Only one functional copy of X chromosome

Question 32

XL inheritance summary

Answer 32

· Genes carried on X chromosome

· Usually only males affected, but female carriers can be affected to lesser degree

• Transmitted (usually) through unaffected females

• No male-to-male transmission

• An affected male cannot have affected sons, but all his daughters will be carriers

Question 33

Genomic imprinting

Answer 33

An epigenetic (non-genetic influence on gene expression) phenomenon that causes genes to be expressed in a parent-of- origin-specific manner

For some genes only 1 out of the 2 alleles is active, the other is inactive. For particular genes it is always the paternal or the maternal allele

Question 34

Homoplasmy

Answer 34

a eukaryotic cell whose copies of mitochondrial DNA are all identical (identically normal or have identical mutations)

Question 35

Heteroplasmy

Answer 35

there are multiple copies of mtDNA in each cell

•the name given to denote mutations which affect only a proportion of the molecules in a cell

•the level of heteroplasmy can vary between cells in the same tissue or organ, from organ to organ within the same person, and between individuals in the same family

Question 36

Mitochondrial genetic disease

Answer 36

Group of disorders caused by dysfunctional mitochondria

Caused by mutations in the mitochondrial DNA (15%)

Caused by mutations in the nuclear genes, whose gene products are imported into the mitochondria

Acquired conditions caused by e.g. drugs

Question 37

Who is mitochondrial DNA (mtDNA) inherited from?

Answer 37

The mother