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?

• 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

Chromosome

Gene

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

Male

Mutations in single genes

Variants in genes

Chromosomal imbalance

Single Gene Disorders

Multifactorial diseases

Chromosome disorders

+ environment

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

Single gene disorders

Recessive

Homozygotes with two copies of the altered gene are affected

Dominant

Heterozygotes with one copy of the altered gene are affected

X-linked recessive

Males with one copy of the altered gene on the X-chromosome are affected

Male

Examples of Autosomal Dominant Conditions• Huntington disease• Neurofibromatosis type 1• Marfan syndrome• Familial hypercholesterolemia• Familial Adenomatous Polyposis (FAP)

Autosomal dominant inheritance

Fig. 3.2 ©Scion Publishing Ltd

Marfan syndrome

(a) Arachnodactyly (long fingers). (b ) Dislocated lens.

Autosomal dominant inheritance

Parents

Gametes

Autosomal dominant inheritance

Parents

Gametes

Autosomal dominant inheritance

Affected Affected Unaffected

Atconception

Examples of Autosomal Recessive Conditions• Sickle Cell disease

• Cystic fibrosis

• Recessive mental retardation

• Congenital deafness

• Phenylketonuria (PKU)

• Spinal muscular atrophy

• Recessive blindness

Autosomal Recessive inheritance

Fig. 1.2 ©Scion Publishing Ltd Photos (a) and (b) courtesy of Dr Tim David

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. 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.

Parents

AUTOSOMAL RECESSIVE INHERITANCE

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

Parents

Sperm/Eggs

AUTOSOMAL RECESSIVE INHERITANCE

A parent who is a carrier passes on either the usual gene

or the altered gene into the eggs or sperm

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

Parents

AUTOSOMAL RECESSIVE INHERITANCE

AffectedUnaffected (carrier)Unaffected

Sperm/Eggs

Unaffected (carrier)

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 albinismOcular albinism• Adrenoleucodystrophy.Adrenoleucodystrophy.

X-Linked Recessive inheritance

Fig. 4.2 ©Scion Publishing LtdPhotos courtesy of Medical Illustration, Manchester Royal Infirmary (a and c), and Andrew Will (b)

Effects of haemophilia

(a) Bleeding around elbow. (b) A retinal bleed. (c) Repeated bleeds into joints produce severe arthritis.

X-linked Recessive Inheritance

One copy of an altered gene on the X chromosome causes the disease in a male.

Male

An altered copy on one of the X chromosome pair causes carrier status in a female.

X XX Y

Female

Daughter Daughter (Carrier) Son Son (Affected)

Parents

Gametes

At conception

X-linked inheritance where the mother is a carrier

Father Mother

XY

XX

(Carrier)(Unaffected)

Multifactorial inheritance• Inheritance controlled by many genes plus

the effects of the environment

• Clinical clue: One organ system affected

• Congenital malformationsCleft lip/palateCongenital hip dislocation Congenital heart defectsNeural tube defectsPyloric stenosisTalipes

• Adult onset disorders Diabetes mellitus Epilepsy Glaucoma Hypertension Ischaemic heart disease Manic depression Schizophrenia

GENETIC ENVIRONMENTAL

Duchenne muscular dystrophy

HaemophiliaOsteogenesis imperfecta

Club footPyloric stenosisDislocation of hip

Peptic ulcerDiabetes

Tuberculosis

PhenylketonuriaGalactosaemia

Spina bifidaIschaemic heart diseaseAnkylosing spondylitis

Scurvy

The contributions of genetic and environmental factors to human diseases

RareGenetics simple

UnifactorialHigh recurrence rate

CommonGenetics complexMultifactorialLow 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

Some medical conditions are caused abnormalities in chromosome number or structure.

Chromosomal abnormalities

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

AutosomesDown syndrome (trisomy 21: 47,XX,+21)

Edwards syndrome (trisomy 18: 47,XX,+18) Patau syndrome (trisomy 13: 47,XX+13)

Sex chromosomesTurner syndrome 45,X

Klinefelter syndrome 47,XXY

All chromosomesTriploidy (69 chromosomes)

Summary of Chromosome Anomalies

• Change in numbere.g. trisomy 21 Down syndrome;

Edwards’ syndrome; Turner syndrome.Usually an isolated occurrence.

• Change in structuree.g. deletionsMay be inherited.

Trisomy 21