enetics% mrs$jones firstconsultation · f...

MCD: Genetics Usama Asif GENETICS 1:

Mrs Jones’ first consultation Dr Alexandra Blakemore ([email protected])

-‐‑ A 35-‐‑year-‐‑old woman, Mrs Jones, comes in for a genetic consultation, because she is 7 weeks pregnant with her first child and is worried about her child. She has heard that 1 in 50 children born have a congenital malformation

-‐‑ Her uncle has haemophilia and her husband’s first cousin has a child with cystic fibrosis -‐‑ She wants to know how at risk her child is, because her mother had four miscarriages and four

normal children -‐‑ We can start by drawing a genetic tree, with Mrs Jones as the proband, the one we’re studying

-‐‑ We can explore congenital abnormalities and chromosomal abnormalities Congenital abnormalities

-‐‑ These are apparent at birth in 1 in 50 of all newborn infants, and account for 20-‐‑25% of all deaths in the perinatal period and childhood up to 10 years

-‐‑ Genetic factors contribute to about 40% of all congenital abnormalities -‐‑ We can class congenital abnormalities:

o Malformation – a primary structural defect e.g. atrial septal defects, cleft lip. There is usually a single organ showing multifactorial inheritance

o Disruption – a secondary structural defect of an organ or tissue e.g. amniotic band causing digital amputation. Usually caused by ischaemia, infection or trauma. Not genetic, but can be predisposed

o Deformation – an abnormal mechanical force that distorts a structure e.g. club foot, hip dislocation. Usually occurs in late pregnancy and has good prognosis because the organ is normal in structure, just oddly shaped

o Syndrome – a consistent pattern of abnormalities with a specific underlying cause e.g. Down syndrome – chromosomal abnormalities

o Sequence – multiple abnormalities initiated by a primary factor e.g. reduced amniotic fluid leads to Potter sequence. Initial factor could be genetic

o Dysplasia – an abnormal organisation of cells in tissue e.g. thanatophoric dysplasia. Caused by a single gene defect, high recurrence risk for siblings/offspring, 1:60000 incidence, FGFR3 mutation, short flat bones, small thorax, large head

o Association – non-‐‑random occurrence of abnormalities not explained by a syndrome. Cause is unknown e.g. VATER association (vertebral, anal, tracheo-‐‑oesophageal, renal)

MCD: Genetics Usama Asif

-‐‑ Classification is not mutually exclusive, e.g. a primary malformation of the kidneys can lead to the same sequence of events as Potter sequence,

Chromosomal abnormalities

-‐‑ Physical characteristics are inherited by parental genes passing down to the offspring -‐‑ From one parent, one inherits:

o Twenty-‐‑two autosomes o One sex chromosome o This is the haploid number (23)

-‐‑ One set of chromosomes is inherited from each parent, giving a total of 46, which is the diploid number

-‐‑ The chromosome looks like an X shape during metaphase -‐‑ The centromere is the point of attachment of the sister chromatids

o If the centromere is exactly in the middle, it is called metacentric o If the centromere is just off middle, it is called submetacentric o If the centromere is not on the middle, it is called acrocentric, with the small ends of the

chromatids called satellites

-‐‑ The normal human karyotype is one that consists of 46 chromosomes in somatic cells and 23 in sex cells. In males, the 23rd pair is XY and in females, it is XX. This is represented as 46,XX in females and 46,XY in males

-‐‑ When they are stained, chromosomes become banded. The short arm is called p and the long arm is called q

-‐‑ Images are done with fluorescent in-‐‑situ hybridisation (FISH) -‐‑ There are different types of chromosomal abnormalities

o Numerical – aneuploidy – loss of gain of a chromosome o Structural – translocations, deletions, insertions, inversions, rings o Mosaicism – different cell lines

-‐‑ Chromosomal abnormalities are present in 60% of early spontaneous miscarriages, 4-‐‑5% of still births, 7.5% of all conceptions and 0.6% of live births

Autosomal aneuploidy -‐‑ This is a numerical abnormality involving the loss or gain of one or more chromosomes:

o Monosomy – loss of a single chromosome, is almost always lethal o Trisomy – gain of one chromosome, is tolerable o Tetrasomy – gain of two chromosomes, is tolerable


-‐‑ Loss of a chromosome gives a 50% reduction of all fully expressed gene products, whereas gain of a chromosome gives a 33% increase of all fully expressed gene products – This is dosage compensation

Partial aneuploidy -‐‑ translocation -‐‑ This is when part of a chromosome is translocated to another chromosome. They can be balanced,

where there is even exchange of genetic material between two chromosomes and no genetic data is lost, or unbalanced, where there is not even genetic exchange, leading to gain or loss of genetic data

-‐‑ For example:

Here, we can see that there is translocation of genetic data from chromosome 3 to the top of one of the chromosome 2 Each chromosome 3 is normal, one chromosome 2 is normal and one chromosome 2 is a derivative, i.e. it has been modified The chromosome 2 derivative was inherited from the father who has a balanced reciprocal translocation i.e. the father had this translocation too, and passed it down to the child This results in trisomy 3, but not total trisomy, only trisomy of the genes that are present on the chromosome 2 derivative Also, there is monosomy 2, but not total monosomy, only where the chromosome 3 has replaced the genetic data of chromosome 2 i.e. Trisomy 3 (p24.2→pter)

Monosomy subtelomeric Chr 2 [46,XX,der(2)t(2;3)(p25.3;p24.2)pat]

MCD: Genetics Usama Asif Examples of trisomy Trisomy 21 – Down syndrome

-‐‑ Overall incidence is 1 in 650 to 700. There is a strong association between incidence and advancing maternal age

-‐‑ Clinical features include: o Newborn period – severe hypotonia, sleepy, excess nuchal skin o Craniofacial – macroglossia (big tongue), small ears, epicanthic folds, upward sloping

palpebral fissures (gap between the upper and lower eyelids), Brushfield spots (white spots in iris)

o Limbs – single palmar crease, wide gap between first and second toes o Cardiac – atrial and ventricular septal defects o Other – short stature, duodenal atresia – abnormally closed

-‐‑ They present with IQs ranging from 25-‐‑75, are happy and affectionate, with relatively advanced social skills, they reach a short height. Cardiac anomalies causes early death in 20% and they have increased risks of leukaemia and Alzheimer’s

-‐‑ It is caused by Trisomy 21 in 95% of all cases, with a 90% maternal origin of the extra chromosome. Caused by non-‐‑disjunction of homologous chromosomes in meiosis I

-‐‑ Can also be caused by translocation in 4% of all cases. It is a Robertsonian translocation, with the breakage of the acrocentric chromosomes (12, 14, 15, 21, 22) and fusion of their long arms

-‐‑ Two thirds have translocation as de novo in the child -‐‑ The other third have their parents as carriers of the translocation -‐‑ This causes a high risk of further Down syndrome babies -‐‑ 13q21q and 14q21q -‐‑ 10% risk of Down -‐‑ 21q21q -‐‑ all offspring will have Down

-‐‑ Can also be caused by mosaicism in 1% of all cases. Children are less severely affected, and caused

by mitotic non-‐‑disjunction in the zygote:


-‐‑ Mosaicism is where not all cells in the body have the genotype causing the affliction

Examples of monosomy Monosomy X – Turner’s syndrome

-‐‑ Incidence: 1 in 3000 live female births -‐‑ Can be detected in the 2nd trimester, where generalised oedema and swelling in neck can be seen -‐‑ They can look normal at birth, or have puffy extremities and intra-‐‑uterine oedema -‐‑ Low posterior hairline, short 4th metacarpals, webbed neck, aorta defect in 15% of cases -‐‑ Normal intelligence -‐‑ In adults, they have short stature and ovarian failure (amenorrhoea and infertility) -‐‑ Treated with oestrogen replacement for secondary sexual characteristics and prevention of

osteoporosis -‐‑ Caused by a loss of the X or Y chromosome in paternal meiosis in 80% of cases -‐‑ Can also be caused by ring chromosome, single arm deletion, mosaicism -‐‑ A ring chromosome is when there are breaks that occur on the ends of the two arms of a

chromosome and the sticky ends are then joined and the fragments are lost. Often unstable at mitosis and so mosaicism is frequent. Some cells have the ring and others are monosomic:

Examples of sex chromosome aneuploidy

-‐‑ Dosage compensation is different in sex chromosomes as only one X is required so the other is switched off in females (X-‐‑inactivation)

-‐‑ Polysomy X in females – 1 in 1000 have 47,XXX with a 10-‐‑20 point decrease in IQ, but present with no physical abnormalities. 95% have an extra maternal X arising in meiosis I, they have normal fertility. There are also 48,XXXX and 49,XXXXX karyotypes, these show mental retardation

-‐‑ Polysomy X in males – o Klinefelter’s syndrome – 47,XXY

1 in 1000 live male births, clumsiness, verbal learning disability, taller than average, 30% develop gynaecomastia (breasts), all are infertile, increased risk of leg ulcers, osteoporosis, and breast carcinoma in later life The extra X can come from a male or a female

o 48,XXXY and 49,XXXXY can happen, but are rare Chromosomal sex and phenotypic gender

-‐‑ Usually, males are XY and females are XX -‐‑ However, it is possible to be chromosomally one gender phenotypically the opposite: -‐‑ The SRY gene causes the development of testes. This can be translocated to the X chromosome in

SRY recombination -‐‑ XX males develop testes but are sterile because some genes on the Y chromosome are needed for

spermatogenesis. XY females are infertile


Genomic disorders Di George syndrome

-‐‑ Velocardiofacial (VCFS)/Sedlackova syndrome -‐‑ Variable symptoms

o Congenital Heart Disease o Palatal abnormalities o Thymic/Parathyroid Hypoplasia o Characteristic Facies o Learning Difficulties

-‐‑ Commonest microdeletion disorder -‐‑ Approx 1/4000 live births -‐‑ Hemizygous Microdeletion of 1.5-‐‑3 Mb of 22q11 -‐‑ Detect using TUPLE1 gene probe and FISH

Cri du Chat syndrome -‐‑ Characteristic Facies:

o Microcephaly, Hypertelorism, Micrognathia, Epicanthal folds, Low-‐‑set ears, Hypotonia -‐‑ Severe psychomotor and mental retardation -‐‑ Characteristic cat-‐‑like cry in newborns -‐‑ Rare – Approx 1 in every 50000 live births -‐‑ Deletion varies from 5p15.2 to whole of 5p

Mrs Jones’ first consultation, results

-‐‑ She has elevated risks of miscarriage and congenital abnormalities because of her age and family history. We need to further investigate the fact that she has mentioned haemophilia and cystic fibrosis within her family


Mrs Jones 2:

Risk of transmission of genetic disease Dr Jess Buxton ([email protected])

-‐‑ A genetic disease is an illness with a genetic component, with changes in the germ line -‐‑ Before we can assess Mrs Jones’ risk of having a baby with either cystic fibrosis or haemophilia,

we need to take a family history and see the pattern of inheritance and mechanisms of these conditions

-‐‑ Genetic diseases can be either monogenic or complex o Monogenic disorders are familial, have a mode of inheritance and can be common or

rare o Complex disorders are sporadic or familial, they can also be caused by environmental

factors, and are common disorders e.g. type II diabetes, obesity, Parkinson’s -‐‑ Focus on monogenic -‐‑ Mendelian Inheritance is the process whereby individuals inherit and transmit to their

offspring, one out of the two alleles present in their homologous chromosomes -‐‑ An allele is an alternate form of a gene or a DNA sequence at the same chromosome location

(locus) -‐‑ Homologous chromosomes are a matching (but non-‐‑identical pair) or chromosomes. Different

alleles may be described as mutations or polymorphisms -‐‑ A mutation is any heritable change in the DNA sequence -‐‑ A polymorphism is a >1% frequency of a mutation in a given population, but are called

mutations if they cause a monogenic disease. They may contribute to complex diseases -‐‑ Mutations can be point mutations (missense – where one amino acid is replaced by another;

nonsense – where the polypeptide is stopped prematurely) -‐‑ They can also be frameshift mutations (insertion – one base inserted into the genome; deletion –

one base deleted from the genome) and affects all the sequence after. It is put out of frame Taking a family history

-‐‑ This is important to: o Identify genetic disease running in family o Identify inheritance patterns o Aid diagnosis o Assist in management of condition o Identify relatives at risk of disease

-‐‑ We can do this by drawing a family pedigree -‐‑ Build it up from the bottom, starting with affected child and siblings, record names and dates of

birth -‐‑ See slides for the rules of pedigree diagram

Mendelian inheritance patterns

-‐‑ Autosomal dominant -‐‑ Autosomal recessive -‐‑ X-‐‑linked -‐‑ Complications…


Autosomal dominant -‐‑ At least one parent is affected -‐‑ Can be transmitted by male of female -‐‑ Vertical transmission -‐‑ Male or female can be affected -‐‑ 50% of offspring are affected For example: Huntington’s disease -‐‑ Mean age of onset is 35-‐‑44 years, causes motor, cognitive and psychiatric dysfunction –

hyperkinesia -‐‑ Median survival time is 15-‐‑18 years after onset -‐‑ Treatment eases symptoms, no cure -‐‑ Caused by inheritance of a mutated HTT gene on chromosome 4 that encodes for a protein

called huntingtin. This mutated gene encodes toxic forms of huntingtin that form clumps in the brain. There is cell death in the basal ganglia in the brain eventually, that leads to symptoms

-‐‑ Dominant anticipation is the increase in severity and/or earlier onset of symptoms seen in some diseases e.g. Huntington and myotonic dystrophy

-‐‑ Huntington’s disease is caused by an unstable triplet repeat, the number of repeats expand with each generation

-‐‑ The repeat is CAG, codes for glutamine

o 10-‐‑35 repeats, the person is unaffected o 27-‐‑35, unaffected, but at risk of having an affected child o 35-‐‑40, sometimes affected, sometimes not o 40-‐‑120 – affected

Autosomal recessive -‐‑ No affected parent -‐‑ Transmitted and affects either males of females -‐‑ Usually no family history -‐‑ 25% of offspring are affected -‐‑ 50% inherit one copy of the defective gene

-‐‑ These types of diseases appear more frequently in consanguineous families due to the fact that

the proportion of the allele in the population rises


For example: cystic fibrosis -‐‑ A multi-‐‑system progressive and variable condition. Individuals are differently affected by the

severity of its symptoms -‐‑ Thick mucus in lungs causes breathing problems and repeated infections -‐‑ Blockages in pancreas affect digestive enzymes -‐‑ Treatment consists of daily enzymes and physiotherapy -‐‑ In the UK, 1 in 22 people are CF carriers -‐‑ Caused by inheritance of a mutated form of the CFTR gene on chromosome 7 that encodes for

a protein called the CF transmembrane conductance regulator -‐‑ CF patients inherit two copies of the mutated form of this gene, which causes the absence of

any working CFTR protein. This affects chloride ion channel function in ‘wet’ epithelial cells, causing disruption of salt/water regulation causes lack of water in mucus, causing thick mucus and hence the symptoms

-‐‑ There are over 1000 mutations identified, with the most common being in ΔF508

-‐‑ Mutations in this gene can cause a different disease: congenital absence of the vas deferens, is a condition in which the vas deferentia fail to form properly. This causes infertility, and affects 1 in 2500 men. Most cases are caused by a mutation in the CFTR gene

X-‐‑linked -‐‑ No affected parents -‐‑ Only males affected -‐‑ Transmitted by a carrier female -‐‑ 50% of sons are affected -‐‑ 50% of daughters are carriers

For example: Haemophilia -‐‑ This is a blood clotting disorder, and affected people bruise easily. There are two types:

haemophilia A and haemophilia B. Can be successfully treated with injections of clotting factor

-‐‑ Haemophilia A is caused by the inheritance of a mutated form of the F8 gene on the X-‐‑chromosome that encodes a protein called coagulation factor VIII. This leads to a lack of functioning factor VIII, leading to the symptoms

-‐‑ Haemophilia B is caused by mutations in the F9 gene, also on the X-‐‑chromosome, which codes for a protein called coagulation factor IX, same symptoms as haemophilia A but is much rarer

MCD: Genetics Usama Asif Genetic heterogeneity

-‐‑ Same gene, different mutations, different diseases – e.g. cystic fibrosis and CAVD are both caused by mutations in the CFTR gene

-‐‑ Same disease, different genes – e.g. Haemophilia A (mutations in F8 gene) and Haemophilia B (mutations in F9 gene)

-‐‑ Same disease, different genes, different inheritance patterns – e.g. different forms of epidermolysis bullosa can be autosomal dominant or autosomal recessive

Simple Mendelian inheritance patterns can get complicated

-‐‑ Penetrance – frequency with which symptoms are present in an individual who inherits a disease-‐‑causing mutation

-‐‑ Variable expressivity – degree of severity in an individual who inherits a disease causing mutation

-‐‑ Phenocopy – disease with the same phenotype as a genetic disease, but non-‐‑genetic -‐‑ Epistasis – interaction between disease gene mutations and other modifier genes can affect the

phenotype Mechanisms of genetic disease

-‐‑ Dominant conditions are usually caused by genes that result in a toxic protein (e.g. huntingtin) i.e. the effects of the mutated protein mask the normal copy. Therefore, one needs to counter the effects of the toxic protein or neutralise it, or switch off the mutant gene

-‐‑ Recessive conditions are caused by the absence of a working gene (e.g. CF, haemophilia), i.e. the effects of the mutated gene are only seen when the normal copy is absent. Therefore, one needs to restore activity of the missing protein by replacing genes, protein, or the affected tissues

-‐‑ Co-‐‑dominant conditions – the effects are both apparent in people e.g. sickle cell trait Mrs Jones’ second consultation, results

-‐‑ Her paternal uncle as haemophilia, so the chance of her son to have haemophilia is the same as the chance it would take to cause a mutation in the gene. If it had been her maternal uncle, she could have been a carrier

-‐‑ Her husband’s first cousin has a child with cystic fibrosis. Thus, her husband has a 1 in 8 chance of being a carrier. She herself has a 1 in 22 chance of being a carrier, so if both are carriers, there is a 1 in 4 chance the child is affected. The over all chance of the foetus being affected with cystic fibrosis is thus 1 in 704 (1 in 22 times 4 times 8)


More stories from the Genetics Clinic Dr Jess Buxton ([email protected])

1. Imprinting Disorders – Prader-‐‑Willi, Angelman

-‐‑ A few genes are only expressed via the maternal or paternal allele. The other allele is permanently switched off. The genome has an imprint of parental origin

-‐‑ Parental origins of chromosomes are important, for example, 46,XX, where the genome is entirely from the maternal genome forms an ovarian teratoma, whereas if the genome is entirely from the paternal genome, it forms a hydatidiform mole

-‐‑ Imprinting is a reversible epigenetic effect, DNA methylation is the mechanism -‐‑ Prader-‐‑Willi and Angelman syndromes are two distinct clinical syndromes, but they are

caused by the same chromosomal region on chromosome 15 -‐‑ However, they are distinct in that they result from the loss of function of one of the two

parental chromosomes -‐‑ If the paternal chromosomal region is damaged or not present, then Prader-‐‑Willi syndrome is

phenotypically presented. If it is the maternal chromosomal region, then Angelman syndrome manifests

Prader-‐‑Willi syndrome

-‐‑ Symptoms include:

o Muscle hypotonia o Hyperphagia o Obesity/diabetes o Mental retardation o Short stature o Small hands and feet o Delayed/incomplete puberty o Infertile

-‐‑ It has a birth incidence of 1:10000 to 1:25000 -‐‑ Hyperphagia is managed by diet restriction -‐‑ Exercise is done to increase muscle mass -‐‑ Growth hormone is given to treat for short stature -‐‑ Hormone replacement is given for puberty -‐‑ It is caused by a lack of a functional paternal copy of the PWS critical region on chromosome

15 (q11-‐‑q13) -‐‑ It happens due to a deletion of the critical region on the paternal chromosome (70%) -‐‑ It can also happen due to inheritance of two maternal copies of chromosome 15 via maternal

uniparental isodisomy (25%) -‐‑ It can also happen due to translocations and point mutations (5%) -‐‑ It is diagnosed with methylation specific PCR -‐‑ With Prader-‐‑Willi syndrome, only the maternal chromosomes will be flagged up


Uniparental isodisomy happens when there is non-‐‑disjunction in meiosis II. This causes one of the sex cells to come out with two copies of the chromosome in it, and one without any copies of the chromosome, and the other two are normal. Fertilisation of the gamete with two copies of the chromosomes with a normal monosomic gamete happens, but the chromosome from the parent contributing the single chromosome is lost, resulting in uniparental isodisomy

Angelman syndrome

-‐‑ Symptoms include:

o Severe developmental delay o Poor or absent speech o Gait ataxia o “Happy demeanour” o Microcephaly o Seizures

-‐‑ Prevalence – 1:10000 -‐‑ Treated symptomatically i.e. with anti-‐‑convulsants, physiotherapy and communication therapy -‐‑ They have a normal life span -‐‑ Same cause, same area, same chromosome as Prader-‐‑Willi syndrome, but this time, involves

paternal uniparental isodisomy

2. Mitochondrial Disorders – MELAS, LHON

-‐‑ Mitochondria are inherited from the mother, because the egg has the mitochondria. The sperm’s mitochondria are all focused on the flagellum that propels it. This means that all mitochondria that the child develops originate from the mother

-‐‑ However, both males and females are affects, because all people need mitochondria


-‐‑ Cells vary in the number of mitochondria they need, -‐‑ Mitochondrial diseases are variable because of heteroplasmy, as not all mitochondria may not

have the disease, it is a sort of mosaicism:

-‐‑ Mitochondrial disorders include: o MELAS – Mitochondrial encephalomyopathy, lactic acidosis, and stroke-‐‑like episodes o LHON -‐‑ Leber’s hereditary optic neuropathy (LHON) o MERRF – Myoclonic Epilepsy with Ragged Red Fibres o DEAF – Non-‐‑syndromic hearing loss o NARP – Neuropathy, Ataxia and Retinitis Pigmentosa

MELAS

-‐‑ This is a progressive neurodegenerative disorder, presenting with muscle weakness, episodic seizures and headache, hemiparesis, vomiting and dementia

-‐‑ There is a prevalence of 1:13000 -‐‑ It is treated symptomatically, and diagnosed with a muscle biopsy -‐‑ It is caused by single point mutations in several genes:

o MTTL1 – tRNA translates codon as phenylalanine instead of leucine during mitochondrial protein synthesis

o MTND1, MTND5 – NADH dehydrogenase

-‐‑ The mitochondrial genome is around 16kb long. It has 37 genes and 13 are responsible for respiratory chain complex. 22 are responsible for tRNA and 2 are responsible for rRNA. There are two to ten copies of the genome per mitochondrion

MCD: Genetics Usama Asif LHON

-‐‑ This is optic neuropathy, loss of sight, most will become blind -‐‑ It is bilateral and painless. There is loss of central vision and optic atrophy -‐‑ The mitochondria in the optic nerve are dysfunctional and thus the optic nerve dies -‐‑ This is much commoner in males for unknown reasons -‐‑ Prevalence – 1:50000 -‐‑ Treated symptomatically -‐‑ Diagnosis is based on ophthalmological findings and a blood test for mtDNA mutations -‐‑ It is caused, over 90% of the time, by mutations in:

o MTND1, MTND4, MTND5, MTND6 and MTCYB – these code for NADH dehydrogenase subunits 1, 4, 5 and 6, and cytochrome b

3. Inborn Errors of Metabolism – Phenylketonuria, MCAD deficiency

-‐‑ Most inborn errors of metabolism are autosomal recessive or X-‐‑linked -‐‑ A few a dominant -‐‑ The defective proteins are manly enzymes -‐‑ The UK Newborn Screening Programme screens newborns for:

o Phenylketonuria o Congenital Hypothyroidism o Sickly cell Disorders o Cystic fibrosis o Medium-‐‑chain acyl-‐‑coA dehydrogenase deficiency

Phenylketonuria

-‐‑ This is caused by the deficiency of the enzyme phenylalanine hydroxylase, causing phenylalanine to accumulate. This is converted into phenylpyruvate, which is excreted in the urine

-‐‑ It also causes a tyrosine deficiency, leading to reduced melanin -‐‑ It manifests with severe mental retardation, and convulsions -‐‑ Phenotypically, people have blond hair, blue eyes and eczema

-‐‑ Early detection by screening for elevated levels of phenylalanine in foetal blood can prevent mental retardation by removing phenylalanine from the diet, but it is a difficult diet to stick to as aspartame contains phenylalanine. Pregnant women need to go back on a diet

MCD: Genetics Usama Asif MCAD deficiency

-‐‑ This is the commonest disorder of fatty-‐‑acid oxidation -‐‑ It is caused by a deficiency of the enzyme medium-‐‑chain acyl-‐‑coA dehydrogenase -‐‑ It causes episodic hypoketotic hypoglycaemia, and presents as early as three months -‐‑ Can present as coma, metabolic acidosis, encephelopahy -‐‑ Sudden death can occur – 25% death rate in undiagnosed cases -‐‑ MCAD is the enzyme that causes dehydrogenation of the acyl-‐‑coA species in the β-‐‑oxidation

cycle in fatty acid metabolism (See metabolism) -‐‑ Thus these people cannot break these fats down, they accumulate and cause problems -‐‑ It is treated by maintaining an adequate calorie intake to prevent the switch to fatty acid

oxidation -‐‑ Fasting is avoided, which is difficult in children who are ill – they need glucose, not fats


Cancer in families and individuals Dr Alistair Reid ([email protected])

1. Understand why genetic changes cause cancer and describe the 2 main classes of cancer gene

-‐‑ Cancer is a genetic disease, it is driven by an accumulation of genetic changes that lead to altered levels of transcription or aberrant gene transcripts

-‐‑ For the majority of cancers, these are so diverse and numerous, only a fraction have been discovered

-‐‑ The resulting proteins change signal transduction pathways that confer a selective advantage to the cell. The affected pathways include those that control cell cycle, apoptosis, cell proliferation and adhesion

-‐‑ Over time, mutations accumulate and result in cancer -‐‑ There are two classes of cancer gene:

o Oncogenes – cause activation or amplification of the cell cycle Normally, oncogenes are responsible for growth and proliferation, e.g. growth factors, transcription factors, tyrosine kinases etc. These are overexpressed in cancers

o Tumour suppressor genes – cause the halting of the cell cycle Normally, they regulate cell division, check for DNA damage and control the cell cycle. They control apoptosis and help in DNA repair. These are deleted or inactivated in cancers

-‐‑ Changes in these genes can occur due to: o Mutations in the promoter

For tumour suppressor genes, they reduce transcription and for oncogenes, they increase transcription

o Mutations in the coding region They truncate or inactivate tumour suppressor genes (this is the main inherited type). They increase activity of oncogenes

o Genomic amplification or whole chromosome gain In oncogenes, they increase gene copy number (aneuploidy or translocations) and therefore transcription

o Genomic deletion or whole chromosome loss In tumour suppressor genes, they are removed (aneuploidy or translocations), either fully or partly, and therefore transcription is reduced

o Gene fusion via chromosome rearrangement In oncogenes, this can cause the formation of a novel protein


-‐‑ Techniques are used to detect different types of abnormalities: o Cytogenetic changes are detected by microscopy, i.e. translocations, deletions,

duplications are easily seen o Molecular changes are detected with biochemical tests i.e. PCR, southern blotting etc.

2. Understand the contribution of chromosome rearrangements to the formation of gene fusions and their contribution to oncogenesis

-‐‑ Chromosome rearrangements can lead to gene copy number changes via deletion or duplication

-‐‑ They can also cause gene fusion, via translocation or inversion

-‐‑ Most tumour suppressor genes require inactivation of both alleles to cause malignancy. The first mutation is often caused by a mutation and the second is usually caused by a deletion

-‐‑ The first mutation usually reduces the transcription level, but is insufficient to produce a phenotypic effect. The second allele needs to be inactivated also, which causes a total loss of transcription for the malignant phenotype to be conferred

-‐‑ Some only need one allele to be effected – haploinsuffiency:


-‐‑ Loss of heterozygosity (LOH) is has several related meanings: o A historical method of assessing the stability of cancer genomes and looking for the

location of TS genes o Another term for deletion o Unmasking of the mutated copy of a TS gene

-‐‑ LOH describes a region of apparent homozygosity, probably via a deletion in cancer tissue, that may mark the location of a tumour suppressor gene

3. Explain the difference between somatic and germline mutations

-‐‑ 99% of cancers are sporadic or non-‐‑inherited. The remaining 1% are inherited i.e., they have a germline component

-‐‑ The vast majority of cancer cases are caused by acquired changes in somatic tissue via somatic mutations i.e. mutations acquired via the environment

-‐‑ There are very few cancers that are initiated from one parent, or sometimes both, of a mutation in germline tissue, usually a tumour suppressor gene, via germline mutations i.e. inherited mutations. In inherited cancers, the risk is cancer is higher than normal but not 100%, because additional somatic changes are needed, i.e. the first mutation in the TS gene may be via a germline mutation, but the second one will almost always be a somatic mutation, leading to the cancer. Thus, one can be predisposed to a certain type of cancer, but not ever get it


4. Discuss how inherited mutations in BRCA1 and BRCA2 genes influence risk of breast and ovarian cancer

-‐‑ 2-‐‑4% of breast cancer cases are caused by a germline mutation of BRCA1 and BRCA2 genes i.e. the first hit is a germline mutation in these genes

-‐‑ 60% of these are at risk of developing cancer by age 90, and they have an earlier average age of onset than those without this germline mutation

-‐‑ The inactivation of the second allele is usually by a somatic deletion -‐‑ There is also an increased risk of developing ovarian cancer – they are also predisposed to this -‐‑ BRCA2 mutations also predispose breast cancer to men -‐‑ The mutation can occur anywhere in the BRCA exon structure, including but not limited to

point mutations. They result in a truncated non-‐‑functional protein -‐‑ BRCA1 and BRCA2 normal function is DNA repair, via a process called homologous

recombination. A truncated or non-‐‑functional protein causes impaired DNA repair, so mistakes or damage go uncorrected

5. Outline how defects in cell division or DNA repair influence risk of colorectal cancer

-‐‑ There are two common colorectal syndromes that are caused by the inheritance of one mutated allele of a tumour suppressor gene:

o Familial adenomatous polyposis (FAP) Characterised by the growth of many intestinal polyps, one or more of which is likely to become cancerous. It accounts for >1% of all colorectal cancers. Caused by a mutation in the APC gene, which controls cell division. This mutation almost always confers cancer in later life

o Hereditary non-‐‑polyposis colorectal cancer (HNPCC or Lynch syndrome) 3% of all cases, this is the most common inherited form (90% of familial cases). The mutation is in MLH1 and MSH2 genes, which are DNA repair genes, and comes with an 80% risk of developing cancer in later life

-‐‑ For patients with inherited cancer syndromes, they can be given genetic screening and

counselling to see if they are mutation-‐‑positive, if they are, they can be prophylactically treated, surveyed and given chemopreventative medications

6. Explain, using an example, how chromosome translocations are used to quantify residual disease in some leukaemias

-‐‑ Sporadic malignancies are acquired chromosome abnormalities and oncogenic fusion genes are disease markers in patient management

-‐‑ Cancer genomes have cytogenetic changes as well as molecular changes associated with them -‐‑ These abnormalities can be causal or accumulate during disease progression -‐‑ Cytogenetic changes are seen in malignant tissues, below is a karyotype of a cell that is

abnormal:


-‐‑ Haematological malignancies – lymphomas and leukaemias -‐‑ Chronic myeloid leukaemia – this is a clonal myeloproliferative disorder of the pluripotent

haematopoietic stem cell leading to an overproduction of mature granulocytes i.e. neutrophils and monocytes

-‐‑ It is triphasic, with a chronic stage, an accelerated stage and a terminal acute stage -‐‑ The consistent pathogenic marker is a translocation between chromosomes 9 and 22 – t(9;22) –

resulting in a fusion gene called BCR-‐‑ABL1:

-‐‑

-‐‑ This is the hallmark of CML, the BCR-‐‑ABL1 fusion gene resides on the Philadelphia chromosome and codes for a tyrosine kinase

-‐‑ To treat this then, a tyrosine kinase inhibitor is needed – Imatinib (Glivec) -‐‑ But 20-‐‑30% patients lose response and require a second tyrosine kinase inhibitor, so monitoring

is important for disease management -‐‑ Genetics methods can be used to detect leukaemia in patients using:

o Conventional cytogenetics – to look for the Philadelphia chromosome via G-‐‑banding karyotypes

o Fluorescent in-‐‑situ hybridisation (FISH) – to look for the juxtaposition of BCR and ABL by looking at different colours on the karyotype that are highlighted. Fusions of BCR and ABL will be seen as BCR positive and ABL positive very close together:

o PCR – to look for BCR-‐‑ABL mRNA using PCR -‐‑ Disease burden is reduced over time, so there are certain time gaps the

methods can be used in -‐‑ This can be used to indicate when a new therapy method is needed

-‐‑ Acute promyelocytic leukaemia is the abnormal accumulation of immature

granulocytes called promyelocytes -‐‑ It is characterised by a chromosomal translocation in the retinoic acid receptor

(RARα) gene on chromosome 17 and the promyelocytic leukaemia gene on chromosome 15 – t(15;17) (q22;q12)


-‐‑ RARα is a member of the nuclear family of receptors. Retinoic acid, its ligand, is a form of vitamin A and acts as a regulator of DNA transcription

-‐‑ The translocation product is the PML-‐‑RARα fusion protein, which binds too strongly to DNA via an enhanced interaction with co-‐‑repressor molecules, and blocks transcription, so can affect the TS genes

-‐‑ This type of leukaemia response to all trans-‐‑retinoic acid (ATRA) therapy, a vitamin A derivative. It dissociates co-‐‑repressors allowing normal translation and cell differentiation. ATRA therapy isn’t the same as other chemotherapy; it does not kill cells. It is effectively when taken continuously, but residual stem cells remain

-‐‑ It is monitored like chronic myeloid leukaemia, with cytogenetics, FISH and PCR

7. Explain with examples what is meant by a “pharmacogenomic marker”

-‐‑ Pharmacogenomics is an emerging branch of pharmacology that deals with the influence of genetic variation on drug response

-‐‑ In cancer treatment, pharmacogenomics tests are used to identify which patients are most likely to respond to certain drugs based on the presence or absence of particular somatic mutations

-‐‑ For example: o KRAS test with cetuximab for colorectal cancer

KRAS mutation = less likelihood of a response o EGFR test with gefitinib for non small-‐‑cell lung cancer

EGFR mutation = greater likelihood of response o BCR-‐‑ABL1 “T315I” test with dasatinib for chronic myeloid leukaemia

BCR-‐‑ABL1 T315I mutation = unlikely to respond


Prenatal diagnosis of genetic diseases Mr Ruwan Wimalasundera ([email protected])

1. Indications for Prenatal Diagnosis

-‐‑ Prenatal testing is done for the benefit of the mother. Known genetic disorders are tested for with Down syndrome being the most common genetic defect tested for

-‐‑ Prenatal testing is done when indicated by a high risk of aneuploidy, as shown by: o A high risk on Down syndrome testing o A previous aneuploidy foetus o Maternal request

-‐‑ It is also done when indicated by a known genetic disorder e.g. o Achondroplasia o Cystic fibrosis o Haemoglobinopathies o X-‐‑linked disorders o Parental balanced translocation

-‐‑ And finally, it is also done when there is a structural anomaly detected in the foetud on routine ultrasound screening

2. Antenatal Screening for Aneuploidy (Down Syndrome)

-‐‑ Down syndrome is the most common genetic defect and is incident in 1 in 700 pregnancies, it isn’t inherited

-‐‑ It is associated with birth defects -‐‑ It has variable severity, and is not predictable -‐‑ Caused by trisomy 21 caused by a non-‐‑disjunction, translocation or a mosaicism -‐‑ The risk increases with a woman’s age because the ova number decreases so the proportion of

abnormal ova, if any, increases -‐‑ Risk of Down syndrome increases with nuchal translucency also, as the foetus has more fluid

below its neck on scanning, which is indicative of Downs -‐‑ Down screening tests:

o Triple test – use AFP, unconjugated oestriol and hCG together with maternal age to gauge a risk

o Nuchal translucency test (NT scan) – measures the fold of the skin on the back of the foetal neck with the maternal age to gauge a risk

o Quadruple test – same as triple, but also looks at inhibin-‐‑A for a measurement of risk o Combined test – NT measurement with free β-‐‑hCG, PAPP-‐‑A and maternal age (all signs

of Down syndrome risk) to measure risk o Integrated test – Integrates NT measurement and PAPP-‐‑A in the first trimester with

serum AFP, free β-‐‑hCG, oestriol and inhibin A in the second -‐‑ The combined test screens the earliest and most accurate. There is a correction factor for

monochorionic and dichorionic -‐‑ The above tests are high-‐‑risk tests that rest for a risk of having Downs -‐‑ One can test invasively if someone is high risk


3. Prenatal Testing – amniocentesis, chorionic villus sampling, foetal blood sampling, elective late karyotyping Amniocentesis

-‐‑ Amniocentesis is the extraction of amniotic fluid from the amniotic sac during pregnancy. The fluid contains the child’s urine and cells that can be tested

-‐‑ This is performed any time after 15 weeks -‐‑ Use the aseptic technique, and try to avoid the placenta -‐‑ Complications include:

o Pregnancy loss – 1% miscarriage o Rh sensitisation – see later, all Rh negative women get Anti D within 72h o Liquor leakage o Infection o Late diagnosis

-‐‑ Can conduct a cytogenetic analysis, where the foetal cells are concentrated in a centrifuge and cultured

-‐‑ If one finds mosaicism, which is two or more cell lines (cultures) with different chromosomal constitutions. Need to make sure, so it needs to be two different cultures. Mosaicism is true

-‐‑ Need to look at multiple chromosomes using quantitative fluorescent PCR Chorionic villus sampling

-‐‑ This takes a sample from the placenta and can be used before 15 weeks, from 11 weeks onward, via a transabdominal needle or cervical

-‐‑ Ideal for DNA analysis -‐‑ Need to avoid Rh sensitisation -‐‑ Risk of miscarriage = 0.5-‐‑2% -‐‑ Can lead to limb defects -‐‑ Can test cytogenetically, with syncytiotrophoblast/cytotophoblast cells already dividing, so a

direct culture is possible in 72h, they are cultured for 14 days and used to check for any abnormalities. There is a 0.03% false negative rate. Mosaicism is confined to the placenta

Foetal blood sampling

-‐‑ This is taking a blood sample from the foetus directly. This tests for foetal anaemia and needs to be done in aseptic conditions

-‐‑ The mode of entry is into the intrahepatic vein or into the umbilical cord -‐‑ Loss rate is 0.9%

Rhesus sensitisation

-‐‑ The foetus may be Rhesus positive and the mother may be Rhesus negative. The baby will become anaemic is the antibodies from the mother get into the baby, so the mothers are given anti-‐‑D to prevent this

-‐‑ The antibodies that the mothers produces against the Rhesus protein if it gets into her blood will pass into her baby’s blood and they will bind to the baby’s Rhesus protein on its red blood cells. This will be attacks by the baby’s immune system, rendering them anaemic


4. Cytogenetic Techniques

-‐‑ Can use fluorescent in situ hybridisation (FISH) using fluorescently labelled DNA probes. It is chromosome specific

-‐‑ And PCR -‐‑ Genetic prenatal diagnoses need to be balanced between the risk of the condition and the risk

of the procedure -‐‑ For example, elective late karyotyping, avoids the risk of miscarriage and allows antenatal

diagnosis, but it is late and has low utility, and can cause iatrogenic prematurity -‐‑ Foetal cells in maternal blood -‐‑ Placental RNA produced by the foetus can be tested for an increase in production of proteins

located on say chromosome 21, an overexpression may be an indicator of trisomy 21

5. Management options

-‐‑ Managed by counselling or termination -‐‑ Termination is done if it fulfils the Abortion Act 1967 and the Human Fertilisation and

Embryonic Act 1990: -‐‑ Clause A

The continuance of the pregnancy would involve risk to the life of the pregnant women greater than if the pregnancy were terminated

-‐‑ Clause B The termination is necessary to prevent permanent injury to the physical or mental health of the woman

-‐‑ Clause C The pregnancy has NOT exceeded its 24th week and that the continuance of the pregnancy would involve risk, greater than if the pregnancy were terminated, of injury to the physical or mental health of the pregnant women

-‐‑ Clause D The pregnancy has NOT exceeded its 24th week and that the continuance of the pregnancy would involve risk, greater than if the pregnancy were terminated, of injury to the physical or mental health of any existing children of the family of the women

-‐‑ Clause E There is substantial risk that if the child were born it would suffer from physical or mental abnormalities as to be seriously handicapped,

-‐‑ Most are done under C and D (93%) -‐‑ Some are done under E (e.g. 96% of cases of trisomy 21 and spina bifida) -‐‑ If the pregnancy is chosen to continue, then parents are supported, and are offered monitoring.

They make detailed plans for delivery, labour, neonatal resuscitation, post-‐‑mortem, postnatal care etc.

-‐‑ They are also offered genetic counselling to be informed of the risk of recurrence and management of future pregnancies, and implications to other family members


Complex genetic diseases – can genes make us fat? Dr Alexandra Blakemore ([email protected])

1. Introduction to genetics of obesity: syndromic, monogenic, common obesity

-‐‑ Fat is a necessary storage of energy and water -‐‑ It provides insulation and supports and protects vital organs -‐‑ It is a source of hormones, and is a regulator of reproduction. It is especially important in sexual

signalling -‐‑ It also has a role in the immune system and aids wounds healing -‐‑ Not having enough fat is a bad thing, and leads to infertility, miscarriage, and death from

infections etc. -‐‑ We have a complex system to regulate our body fat levels, it is called the adipostat -‐‑ BMI is used to calculate where one is on the obesity scale -‐‑ Ethnicity is important as Asians have a lower BMI but a higher percentage body fat compared to

Caucasians -‐‑ Body weight is affected by muscle/fat ratio as muscle is heavier than fat -‐‑ Obesity is defined has having a BMI of over 30 and morbid obesity is over 40 -‐‑ There are increasing obesity rates -‐‑ Not everyone is overweight though -‐‑ There are syndromic obesities, monogenic obesities and common obesities -‐‑ Genetics affects individual responses to the obesogenic environment -‐‑ Obesity is caused by a number of factors:

o Lack of physical activity o Gene variations o Stress o High density calorie diet

-‐‑ Essentially, we get fat by our behaviour, our physiology (metabolism etc.) and it is controlled by our genes that control our adipostat

-‐‑ To gain 1lb of fat a year, we only need 10 extra calories a day, which isn’t gluttony, it’s that our appetites need to be very highly regulated to be perfect

Syndromic obesity

-‐‑ There are around 30 known syndromic forms of obesity, i.e. those that are usually accompanied by mental retardation, and particular dysmorphic or clinical features

o Prader-‐‑Willi syndrome is the most common – imprinting defect, see earlier lecture Monogenic obesity

-‐‑ All monogenic forms of obesity known so far affect appetite regulation -‐‑ Monogenic obesity are dominant or recessive single gene disorders -‐‑ Leptin – the first obese gene. This is a blood-‐‑borne factor that controls appetite and stops people

eating. The levels of this protein in the blood are an indicator of how much fat there is in the body

-‐‑ Leptin causes a reduced food intake, reduced insulinaemia and reduced blood sugar


-‐‑ Obese mice were shown to have a lack of or fewer leptin or leptin receptors in the body -‐‑ No leptin in children causes hunger, obesity, no puberty, poor growth, low thyroid function and

immune problems

-‐‑ Most fat people have lots of leptin but may lack or have less receptors than less fat people -‐‑ The adipostat is the leptin-‐‑melanocortin system:

-‐‑ Other genes in the same pathway also cause single-‐‑gene obesity e.g. o PC1 – recessive obesity o MC4R – most common single-‐‑gene form of obesity

-‐‑ All affect appetite regulation

MCD: Genetics Usama Asif Common obesity

-‐‑ Tested for with genome-‐‑wide association studies (GWAS), which is hypothesis-‐‑free, “common disease, common variant”

-‐‑ Looked at single nucleotide polymorphisms throughout the genome of people with common obesity and the GWAS identified SNPs only explain a small proportion of common obesity risk

-‐‑ It has only identified associations that are statistically strong and reliable, but the genetic component contribution is low, <5%

-‐‑ More work is needed

2. Identification of GSVs in “obesity-‐‑plus” patients 3. Implications for common obesity

-‐‑ The heritability of complex diseases could maybe be due to rare variants or even genomic

structural variation (GSV) or even epigenetics -‐‑ Patients with syndromic forms of obesity have more GSVs, i.e. threefold more deletions, more

than 500kb more than control populations -‐‑ Large GSVs are found in patients with obesity-‐‑plus phenotypes can be used to identify new

obesity loci. These loci can be investigated in the general population to find rare variants -‐‑ Variations can include deletions, duplications (amplifications), inversions or translocations -‐‑ We all have many GSVs, some have no effect, but others are associated with ill effects -‐‑ For example, a deletion on chromosome 16p11.2 in a patient with ‘obesity-‐‑plus’ phenotypes

caused some mental retardation, poor speech, congenital nystagmus, squint, etc. -‐‑ This deletion is observed in patients with neurocognitive problems -‐‑ The deletion is more common in ‘obesity plus’ patients -‐‑ It is the first GSV (copy number variation) directly associated with obesity -‐‑ Duplications (the opposite) were reported to be associated with schizophrenia, and other

mental illnesses “Convincing obesity association for deletions of the ~700kb 16p11 ‘autism’ locus Onset of obesity at 8-‐‑10 years of age Explains ~1% of adult morbid obesity in the general population Duplication carriers are more likely to be underweight Strong association with child obesity of nearby 220kb deletion encompassing SH2B1 Explains >0.5% of child morbid obesity cases Impact on adult obesity is less clear”

4. Prospects for personalised medicine

-‐‑ Around 1:20 morbidly obese people have a highly penetrant Mendelian form of obesity -‐‑ They are rarely offered screening or counselling e.g. for obesity of autism risk -‐‑ They can be offered a choice of medications that help, new drug development and there is the

potential for intensive lifelong preventative intervention and they can choose their surgery if needed

Key point: Common diseases may have a range of causes, some very strongly genetic. Progress in genetics is fast, Genetic causes do not imply that there is nothing that can be done. Evidence-‐‑based medicine must be used and must not be suspended because patients are stigmatised


The future of genomic medicine Dr Jess Buxton ([email protected])

1. Advances in genomic medicine What we know now

-‐‑ We know about chromosome abnormalities that cause congenital conditions -‐‑ Genetic mutations have been identified for many monogenic disease -‐‑ As a result, in the UK, antenatal screening is offered for all pregnant women. Genetic tests and

counselling is offered for families affected and there is the Newborn Screening Programme -‐‑ The entire DNA sequence of the human genome has been determined -‐‑ Extensive genetic variation has been identified, both by single base pair changes and structural

variants -‐‑ There are some common and rare genetic variants that affect risks of complex disease

What we don’t yet know

-‐‑ We don’t know what all the DNA codes for in humans -‐‑ We don’t know the causes of some rare monogenic diseases -‐‑ We don’t know genetic variants that affect different drug responses -‐‑ Most of the DNA variants that affect risk of complex disease, we don’t know -‐‑ And we also do not know how genetic and environmental factors interact to affect risk of

complex disease a. ‘Next generation’ DNA sequencing b. Finding the causes of monogenic disease

-‐‑ The entire genome cost loads to sequence. Now it could be done cheaply very soon -‐‑ Next generation sequencing is used to identify novel gene mutations in monogenic disease -‐‑ Whole exome sequencing – just protein coding genes

o WES helped to determine the genes that caused Miller syndrome (DHODH gene) and Schinzel-‐‑Giedion syndrome (SETBP1 gene)

c. Pharmacogenetics

-‐‑ Studying the genetic basis for the difference between individual response to drugs can lead to

the right drug being administered at the right dose for the right patient -‐‑ For example, variants in the TPMT gene affect the metabolism of the drug, 6-‐‑mercaptopurine.

People with low activity of TPMT are at risk of bone marrow toxicity if the drug is given -‐‑ Maturity onset diabetes of the young (MODY) can be misdiagnosed as Type I diabetes, and

the drugs used to treat them are different – metformin for MODY and insulin for Type I

d. Risk of common, complex diseases

-‐‑ Many genetic variants that affect the risk of common, complex traits and diseases are identified through Genome Wide Association Studies (GWAS) (See previous lecture)


2. Personalised healthcare a. Direct-‐‑to-‐‑consumer genetic testing

-‐‑ Genetic information can be sold -‐‑ Some companies are already offering disease-‐‑specific tests directly to consumers -‐‑ For monogenic disease, direct to consumer genetic tests can provide:

o Carrier status information e.g. Tay-‐‑Sachs, cystic fibrosis o Detection of rare resinous conditions in newborns e.g. MCAD deficiency o Genetic counselling (must be provided) o Determination of later onset disease e.g. hereditary breast cancer

-‐‑ For complex disease o May cause alarm o May offer false reassurance o Data privacy concerns o Limited clinical utility as treatments are rare

Can help in the prediction of common disease – e.g. Type II diabetes – caused by the complex interaction of environmental factors and genetics = strongest gene with variants is the TCF7L2 gene b. Ethical issues

-‐‑ Tests of dubious clinical benefit may be offered -‐‑ Test results may cause false alarm -‐‑ May provide false reassurance -‐‑ Complex results may not be explained fully or with appropriate genetic counselling -‐‑ Data protection concerns -‐‑ Commercial genetic testing for disease risk based on incomplete information -‐‑ Right ‘not to know’ (particularly children) -‐‑ Protection of data, right to ‘genetic privacy’ -‐‑ Equality of access to genetic information

c. Future perspectives

-‐‑ Whole genome sequencing can replace individual genetic tests for variants to examine all

variants (both common and rare) in one analysis

3. Embryo testing a. Pre-‐‑implantation genetic diagnosis (PGD)

-‐‑ PGD is a genetic test carried out on IVF embryos usually to ensure that only embryos free from

a genetic condition are returns to the woman’s womb

b. Uses and limitations

-‐‑ PGD is an option for some families at risk of having a child affected by a serious genetic condition

-‐‑ Can use FISH to detect chromosomal conditions e.g. Down syndrome -‐‑ PCR can be used to detect mutations in single genes


-‐‑ Used to make saviour siblings to select an embryo free from disease and HLA tissue matched for a sibling affected by a disease so allows for easy transplantation

-‐‑ Used for hereditary breast cancer – BRCA1 mutations can be detected and avoided -‐‑ Used to avoid early onset and late onset severe genetic diseases e.g. Tay-‐‑Sachs and

Huntington’s respectively -‐‑ Limitations:

o Needs to be done with IVF – emotionally and physically demanding, and expensive o Only suitable for diseases where the genetic abnormality is known o Can only select from traits that are present in the embryos obtained

c. Ethical issues

-‐‑ PGD (like all IVF procedures) involves discarding unused embryos -‐‑ Disability rights arguments -‐‑ ‘Slippery slope’ – designer babies? (not allowed yet) -‐‑ Eugenics -‐‑ Spare part babies?

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