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

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.

Classification of genetic disorders Single Gene Disorders Male Mutations in single genes Multifactorial diseases + environment Variants in genes 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

Heterozygotes with one copy of the altered gene are affected Dominant Heterozygotes with one copy of the altered gene are affected Recessive Homozygotes with two copies of the altered gene are affected Male X-linked recessive Males with one copy of the altered gene on the X-chromosome are 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)

Fig. 3.2 ©Scion Publishing Ltd Autosomal dominant inheritance Marfan syndrome (a) Arachnodactyly (long fingers). (b ) Dislocated lens. Fig. 3.2 ©Scion Publishing Ltd

Autosomal dominant inheritance Parents Gametes

Autosomal dominant inheritance Parents Gametes At conception Unaffected Affected Affected

Examples of Autosomal Recessive Conditions Autosomal Recessive inheritance Examples of Autosomal Recessive Conditions Sickle Cell disease Cystic fibrosis Recessive mental retardation Congenital deafness Phenylketonuria (PKU) Spinal muscular atrophy Recessive blindness

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. 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. 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

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) 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 muscular dystrophy (BMD) Fabry disease Retinitis pigmentosa Alport syndrome Hunter syndrome Ocular albinism Adrenoleucodystrophy.

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.

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 Daughter Daughter (Carrier) Son (Affected) Son

Multifactorial inheritance Inheritance controlled by many genes plus the effects of the environment Clinical clue: One organ system affected 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

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 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. This section 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)

Summary of Chromosome Anomalies Change in number e.g. trisomy 21 Down syndrome; Edwards’ syndrome; Turner syndrome. Usually an isolated occurrence. Change in structure e.g. deletions May be inherited. Down’s Syndrome An example of a chromosomal abnormality which causes learning difficulties The karyotype shows a case of Down’s syndrome (trisomy 21) For more information about Down’s syndrome, visit: www.screening.nhs.uk/downs/index.htm [NOTES FOR TRAINING FACILITATORS IN CASE OF QUESTIONS ONLY In total, there are normally 23 pairs of chromosomes, but in a trisomy there is an extra chromosome (tri somy = three bodies) A normal karyotype is written 46,XY or 46,XX The karyotype, or complement of chromosomes, seen in a regular trisomy 21 is written as 47,XX +21 if female or 47, XY +21 if male Note that Down’s syndrome can be inherited, although this is rare. These cases are due to a change in chromosome structure (a translocation)] Trisomy 21