1. Understanding patterns of inheritance
This presentation builds on session 1 exploring patterns of inheritance

2. Patterns of inheritance
The objectives of this presentation are to:
Understand how genes are inherited
Understand the differences between the inheritance patterns associated with Autosomal dominant, Autosomal recessive, X-linked recessive and chromosomal abnormalities
Understand that the environment can impact on some common complex conditions
Autosomes refer to the first 22 pairs of chromosomes

3. So how are genes passed on from parent to child?
Chromosome
Gene
Genes in the cell nucleus are physically located on 23 pairs of chromosomes
One set of 23 chromosomes is inherited from each parent
Therefore, of each pair of genes, one is inherited from a person’s mother, and one from their father
Diagram showing just one pair of the 23 pairs of chromosomes in the cell nucleus. The location of one of the genes on this chromosome is shown.
For example: ear lobe structure attached or unattached would be located on the same position on the same number chromosome from Mum and Dad

4. Classification of genetic disorders
Single Gene Disorders
Male
Alterations in single genes
Multifactorial diseases
+ environment
Variants in genes
Single Gene – Red represents altered gene in 1st top left pair of Chromosomes 1 altered and 1 unaltered – individual may or may not be affected by this (unless this is a dominant alteration)
2nd pair shows both genes altered – individual will be affected
3rd pair show the sex chromosomes with one alteration but as this is a male XY and the alteration is on the X the male will be affected as there is no counterbalance on the Y chromosome
Multifactoral – Genes rarely act alone e.g. Height they may have the gene for tall but if malnourished may be short. Changes in both genes can have different variants for example the gene for skin colour not just black and white but shades and environment Sun adding further colour or damage.
Chromosomal – Session 1 reminder extra chromosomes plus insertions and deletions
Chromosome disorders
Chromosomal imbalance

5. Single gene disorders
Some medical conditions are caused by a change in just one or both copies of a particular pair of genes. These are called “single gene disorders”.
The three common types of single gene disorders are called:
Autosomal dominant
Autosomal recessive
X-linked
AD – always expresses itself
AR - only expresses in the absence of dominant unaltered gene – healthy carrier
X – genes found on X chromosomes

6. Homozygotes must have two copies of the altered gene to be affected
Dominant
These individuals are called Heterozygotes with one copy of the altered gene they are affected
Recessive
Homozygotes must have two copies of the altered gene to be affected
Hetero means ‘different’, homo means ‘same’
Homozygotes – received an affected chromosome from each parent who may have been healthy unaffected carriers
X-linked – always affected as they don’t have an X to balance the affected chromosome
Male
X-linked recessive
Males with an altered gene on the X-chromosome are always affected

7. Examples of Autosomal Dominant Conditions
Autosomal dominant inheritance
Examples of Autosomal Dominant Conditions
Huntington disease
Neurofibromatosis type 1
Marfan syndrome
Familial hypercholesterolemia
Familial Adenomatous Polyposis (FAP)
Prader-willi
See NGEDC website ‘Search Conditions’ for further information on each of these conditions

8. Fig. 3.2 ©Scion Publishing Ltd
Autosomal dominant inheritance
Marfan syndrome
(a) Arachnodactyly (long fingers). (b ) Dislocated lens.
Marfan syndrome: gene situated on chromosome 15q. Results in tall stature with elongated thin limbs and fingers; high risk of heart defects.
Marfan syndrome has variable expressivity between members of the same family as the protein coded for has different functions within the body.
Fig. 3.2 ©Scion Publishing Ltd

9. Autosomal dominant inheritance
Parents
Gametes
These slides show how and affected dominant gene is inherited by each conception. That this ‘chance’ occurs at each conception is a very important point as a miss-conception “ We have 1 affected child so the next one in a 50:50 chance will be unaffected” is a fairly common occurrence. The same probability is present for each child conceived and is not affected by previous pregnancies.

10. Autosomal dominant inheritance
Parents
Gametes At
conception
Ensuring that the students and therefore the parents understand ‘chance’ is key they need to use what is best for the patient
50:50 or 2 in 4 or 50%
Unaffected
Affected
Affected

11. Examples of Autosomal recessive conditions
Autosomal recessive inheritance
Examples of Autosomal recessive conditions
Sickle Cell disease
Cystic fibrosis
Batten Disease
Congenital deafness
Phenylketonuria (PKU)
Spinal muscular atrophy
Recessive blindness
Maple syrup urine disease
Need both genes in an altered state to show the condition.
See NGEDC website ‘Search Conditions’ for further information on each of these conditions

12. Cystic fibrosis
(a) The outlook for cystic fibrosis patients has improved over the years but they still need frequent hospital admissions, physiotherapy and constant medications. (b) Chest X-ray of lungs of cystic fibrosis patient. © Erect abdominal film of newborn with meconium ileus showing multiple fluid levels. Photos (a) and (b) courtesy of Dr Tim David, Royal Manchester Children’s Hospital.
Cystic fibrosis: the gene is GFTR based on chromosome 7q. It is a defective chloride ion transport in the cell membrane which leads to thickened mucus production outside the cell.
Fig. 1.2 ©Scion Publishing Ltd
Photos (a) and (b) courtesy of Dr Tim David

13. Fig. 4.1 ©Scion Publishing Ltd
Sickle cell disease.
(a) Blood film showing a sickled cell, marked poikilocytosis (abnormally shaped red cells) and a nucleated red cell. (b and c) Bony infarcations in the phalanges and metacarpals can result in unequal finger length.
Sickle cell disease is an altered HBB gene on chromosome 11p. Abnormal haemoglobin is produced which results in sickle shaped red blood cells which can then lead to the blocking of small capillaries.
Fig. 4.1 ©Scion Publishing Ltd

14. AUTOSOMAL RECESSIVE INHERITANCE
Parents
Parent who are carriers for the same autosomal recessive condition have one copy of the usual form of the gene and one copy of an altered gene of the particular pair
The parents are usually healthy carriers
This is not unusual to be a carrier, so many individuals are unaware of their carrier status.
For example 1 in every 12 people in the UK are carriers for the cystic fibrosis gene.

15. AUTOSOMAL RECESSIVE INHERITANCE
Parents
Sperm/Eggs
A parent who is a carrier passes on either the usual gene
The other parent who is also a carrier for the same condition passes on either the usual gene or the altered gene into his/her eggs or sperm
or the altered gene into the eggs or sperm

16. AUTOSOMAL RECESSIVE INHERITANCE
Parents
Sperm/Eggs
Unaffected (carrier)
Unaffected (carrier)
The way to explain ‘chance’ this to the patient or parent is 1 in 4 or 25% chance of being affected or 75% chance of being unaffected 50% chance of being a carrier
Unaffected
Affected

17. Examples of X-Linked Recessive Conditions
X-Linked recessive inheritance
Examples of X-Linked Recessive Conditions
Fragile X syndrome
Haemophilia
Duchenne muscular dystrophy (DMD) (Becker BMD)
Fabry disease
Retinitis pigmentosa
Alport syndrome
Hunter syndrome
Ocular albinism
Adrenoleucodystrophy.
If men have the altered gene they are generally affected. Women with the altered gene may be affected to a varying degree dependant on the activity of the normal gene.

18. Effects of haemophilia
(a) Bleeding around elbow. (b) A retinal bleed. (c) Repeated bleeds into joints produce severe arthritis.
Fig. 4.2 ©Scion Publishing Ltd
Photos courtesy of Medical Illustration, Manchester Royal Infirmary (a and c), and Andrew Will (b)

19. X-linked recessive inheritance
Male
Female X Y X X
One copy of an altered gene on the X chromosome causes the disease in a male.
An altered copy on one of the X chromosome pair causes carrier status in a female.
Female – and may also be affected but this may be reduced depending on the gene involved

20. Y X Parents Gametes X X (Unaffected) (Carrier) Father Mother
X-linked inheritance where the mother is a carrier
Father
Mother Y X
Parents
(Unaffected)
(Carrier)
Gametes X X At
conception
The risk of being affected is dependant on if at conception it is a male or female
Daughter
Daughter (Carrier)
Son (Affected)
Son

21. Polygeneic Inheritance
Single gene disorders are quite rare
Single gene disorders either give risk to a condition or they don’t
Most traits are Polygenic’ i.e. 1 trait coded by a number of altered and unaltered genes working together
The additive effects of 2 or more genes leading to a continuous variation rather than the either /or of a single gene

22. Common Polygenic Disorders
Alzheimer's
Diabetes
Cancer
Eczema

23. Multifactorial inheritance
Inheritance controlled by many genes plus the effects of the environment
Adult onset disorders Diabetes mellitus Epilepsy Glaucoma Hypertension Ischaemic heart disease Manic depression Schizophrenia
Congenital malformations Cleft lip/palate Congenital hip dislocation Congenital heart defects Neural tube defects Pyloric stenosis Talipes
Genes rarely act alone and both single and polygenic can be multifactoral

24. Rare Genetics simple Unifactorial High recurrence rate
The contributions of genetic and environmental factors to human diseases
GENETIC ENVIRONMENTAL
Duchenne
muscular dystrophy
Haemophilia
Osteogenesis imperfecta
Club foot Pyloric stenosis Dislocation of hip
Peptic ulcer Diabetes
Tuberculosis
Phenylketonuria Galactosaemia
Spina bifida Ischaemic heart disease Ankylosing spondylitis
Scurvy
100% genetic
100%
Environmental
Rare Genetics simple Unifactorial High recurrence rate
Common Genetics complex Multifactorial Low recurrence rate

25. Multifactorial
Examples include some cases of cleft lip and palate; neural tube defects; diabetes and hypertension
Caused by a combination of genetic predisposition and environmental influences
Pattern – more affected people in family than expected from incidence in population but doesn’t fit dominant, recessive or X-linked inheritance patterns
Other patterns of Inheritance
Cleft lip and palate is an example of a condition which may have a genetic factor but can also have environmental causes. For example, certain drugs used to treat epilepsy are associated with an increased incidence of cleft lip
Genetic factors underlie many common diseases such as cancer, heart disease and diabetes
When there is significant family history, monitoring and preventative regimens can be offered. Genetic testing is currently very limited but much research is underway

26. Chromosomal abnormalities
Some medical conditions are caused abnormalities in chromosome number or structure.
Chromosome abnormalities was covered in “DNA, genes and chromosomes” presentation in lesson 1. The next 3 slides provides a refresher of the previous lesson.

27. Chromosome anomalies
Cause their effects by altering the amounts of products of the genes involved.
Three copies of genes (trisomies)
= 1.5 times normal amount.
One copy of genes (deletions)
= 0.5 times normal amount.
Altered amounts may cause anomalies directly or may alter the balance of genes acting in a pathway.

28. Most frequent numerical anomalies in liveborn
Autosomes
Down syndrome (trisomy 21: 47,XX,+21)
Edwards syndrome (trisomy 18: 47,XX,+18)
Patau syndrome (trisomy 13: 47,XX+13)
Sex chromosomes
Turner syndrome 45,X
Klinefelter syndrome 47,XXY
All chromosomes
Triploidy (69 chromosomes)