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

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

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

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

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

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

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

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

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.

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

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

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

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

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.

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

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

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.

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)

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

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

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

Common Polygenic Disorders Alzheimer's Diabetes Cancer Eczema

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

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

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

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.

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.

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)