(d) Ante- and postnatal screening. Antenatal screening identifies the risk of a disorder so that further tests and a prenatal diagnosis can be offered. (i) Antenatal screening. Ultrasound imaging. Anomaly scans may detect serious physical problems. Dating scans, for pregnancy stage and due date, are used with tests for marker chemicals which vary normally during pregnancy. Biochemical tests to detect the normal physiological changes of pregnancy. Diagnostic testing Amniocentesis and chorionic villus sampling (CVS) and the advantages and disadvantages of their use. Cells from samples can be cultured to obtain sufficient cells to produce a karyotype to diagnose a range of conditions. Pre-implantation genetic diagnosis (PGD). The use of IVF in conjunction with PGD to identify single gene disorders and chromosomal abnormalities.

View ultrasound images at different stages of pregnancy. View specialised ultrasound images. Examine data on altered blood biochemistry due to altered renal, liver and thyroid function; alterations to carbohydrate and calcium metabolism; and hormonal changes. Examine data on the risks associated with testing for Down’s syndrome. Blood test for alpha-fetoprotein (AFP) and subsequent test for the ‘marker’ nuchal translucency by ultrasound. If the results indicate a high risk of Down’s syndrome further diagnostic tests with more risk may be offered. Construct karyotypes of fetal material which indicate a variety of genetic disorders. Suitable examples include: Down’s trisomy, Edwards trisomy, Klinefelter’s/Turner’s syndromes, Familial Down’s, Fragile X, Cri-du-chat.

Medical conditions can be detected by a range of marker chemicals that indicate a condition but need not necessarily be part of the condition. As a result of routine screening or for individuals in high risk categories, further tests may be offered. In deciding to proceed with these tests, the element of risk will be assessed as will the decisions the individuals concerned are likely to make if a test is positive. Tests may include amniocentesis and CVS from the placenta. CVS can be carried out earlier in pregnancy than amniocentesis. Although it has a higher risk of miscarriage CVS karyotyping can be performed on the fetal cells immediately. Generally mothers show no immune response to their fetus although sensitisation to Rhesus antigens can occur.

Ante and Postnatal Screening

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Ultrasound Imaging Fetus at 12 weeks 1.Stage of pregnancy identification 2. Due date calculation 3. Anomaly scan egnancy-and- baby/pages/screening-tests- abnormality-pregnant.aspx#close

Fetal anomaly scan Name of condition Description of condition How is it diagnosed? What happens next?

Blood biochemistry

Antenatal screening Antenatal screening identifies the risk of a disorder so that further tests and a diagnosis can be offered before birth. Ultrasound imaging: anomaly scans may detect serious physical problems. Dating scans can also identify the stage of pregnancy and due date. Biochemical tests: detecting specific marker chemicals or changes in levels of chemicals in the blood (which vary normally during pregnancy) may indicate a medical condition.

Antenatal screening As a result of routine screening or for individuals in high risk categories, further tests may be offered. These can diagnose and help advise parents of a range of genetic conditions a child may have. Amniocentesis takes foetal cells from amniotic fluid and chorionic villus sampling (CVS) take foetal cells from placenta samples. These can be cultured to obtain sufficient cells to produce a karyotype to diagnose a range of conditions. A karyotype arranges chromosomes into homologous pairs and is used to observe the number and structure of chromosomes. CVS can be carried out earlier in pregnancy but carries a higher risk of miscarriage.

Antenatal screening 1.Name of condition 2.Description of condition 3.Outcome without screening 4.Outcome with screening

Rhesus Antibody Testing Generally mothers show no immune response to their fetus however sensitisation to Rhesus antigens can occur. This can happen when a rhesus negative mother is pregnant with a rhesus positive fetus and a mixing of blood at birth occurs causing sensitisation of the mother to rhesus antigens The immune system of the mother then makes antibodies for the rhesus antigens and memory cells. A second rhesus positive fetus will be attacked through the placenta by the rhesus antibodies from the mother. To avoid this, the mother can be injected with anti- D rhesus antibodies just after the birth of the first child to destroy the rhesus antigen.

Rhesus factor Mothers normally show no immune response to their fetus. Problems may arise if a mother who is Rhesus negative Rh- (does not have the Rhesus antigens on her red blood cells) is pregnant with a Rhesus positive Rh+ foetus (who does have Rhesus antigens on their red blood cells). If red blood cells cross from the foetal blood circulation into the mother's blood during birth, the Rhesus antigens on the foetal cells will be registered as non-self and the immune system is said to be sensitised, making antibodies to destroy the foetal red blood cells. Sensitisation may also result from blood transfusions or damage to the placenta during pregnancy, causing it to leak blood into the mother's system. Should the mother have a second Rh + child, these white blood cells trigger a rapid and large production of antibodies which are small enough to pass across the placenta into the foetus. This results in the destruction of red blood cells in the foetus. Antenatal screening can detect this and so anti rhesus antibodies can be given after a sensitising event or after birth.

Pre-implantation Genetic Diagnosis

Antenatal screening Pre-implantation genetic diagnosis (PGD) involves taking cells from embryos produced from IVF before implantation. Genetic material is extracted from the cells and karyotypes are produced. Single gene disorders and chromosomal abnormalities can then be identified.

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(ii) Postnatal screening. Diagnostic testing for metabolic disorders, including phenylketonuria (PKU), an inborn error of metabolism. New-born screening for other diseases such as galactosaemia, congenital hypothyroidism, amino acid disorders.

Post natal screening

Newborn screening film 5 mins

Heel prick test er.blogspot.co.uk/20 11/04/heel-prick- test.html er.blogspot.co.uk/20 11/04/heel-prick- test.html

Phenylketonuria (PKU) Phenylpyruvic acid – kills brain cells!!!

PKU symptoms behavioural difficulties, such as frequent temper tantrums fairer skin, hair and eyes than siblings without the disease (as phenylalanine is involved in the body's production of melanin, the pigment responsible for skin and hair color) eczema recurrent vomiting jerking movements in arms and legs tremors epilepsy

Galactoaemia

Hypothyroidism

Postnatal screening Blood test occurs days after birth, known as ‘heel prick’ tests. These can diagnose metabolic diseases such as phenylketonuria (PKU), where the baby doesn’t produce an enzyme to break down the amino acid phenylalanine. This is called an ‘inborn error of metabolism’, where a faulty gene doesn’t produce an enzyme in a metabolic pathway. Individuals with high levels of phenylalanine are placed on a restricted low phenylalanine diet.

The use of pedigree charts to analyse patterns of inheritance in genetic screening and counselling. Patterns of inheritance in autosomal recessive, autosomal dominant, incomplete dominance and sex- linked recessive single gene disorders.

Pedigree charts (aka family trees!)

Genetic screening and counselling Pedigree charts (family trees) are used to analyse patterns of inheritance in genetic screening. Once the phenotype for a characteristic is known and a pedigree chart is constructed, most of the genotypes can be determined. This information is used by genetic counsellors to advise parents of the possibility and risk of passing on a genetic condition to their child.

Cystic fibrosis: recessive autosomal condition eature=channel&list=UL eature=channel&list=UL

Autosomal Recessive Inheritance

Autosomal = affects chromosomes (not sex chromosomes) Expressed relatively rarely May skip generations Males and females equally affected All sufferers homozygous recessive Non-sufferers homozygous dominant or heterozygous E.g. cystic fibrosis

Cystic fibrosis N = non sufferer n = cystic fibrosis sufferer P phenotype: non sufferer x non sufferer P genotype: Nn x Nn gametes: N or n x N or n Nn NNNNn n nn F1 genotype: 1 NN: 2Nn: 1nn F phenotype: 3 non sufferers: 1 sufferer

Autosomal Dominant Inheritance

Appears in every generation Each sufferer has an affected parent When a branch of the family does not express the trait it fails to reappear in future generations of that branch Males and females affected equally All non sufferers homozygous recessive Sufferers homozygous dominant or heterozygous E.g. Huntingdon’s disease

Huntingdon’s disease N = Huntingdon’s sufferer n = non sufferer P phenotype: sufferer x sufferer P genotype: NN x Nn Gametes: N or N x N or n NN NNN nNn F1 genotype: 2NN: 2Nn F phenotype: all sufferers

Incomplete Dominance One allele of a gene is not completely dominant over the other. There is an in between state in the heterozygote e.g. sickle cell anaemia. H = normal, S = sickle cells HH alleles = normal SS alleles = red blood cells are sickle shaped (interferes with the circulation and causes death) HS alleles = no sickle shaped red blood cells but they are a carrier of the disease.

Parents: male female P phenotypes: carrier X carrier P genotypes: HS X HS Gametes: H or S X H or S F1: F1 genotypes: 1 HH : 2 HS : 1SS F1 phenotypes: 1 normal : 2 carriers : 1 sickle cell anaemia (deceased) H S H HH HS S HS SS

Revision question 1.A couple, one who is a carrier for the sickle cell trait and another who is homozygous, have children. What is the genotype and phenotype ratio of their offspring? 2.A man whose parents are both heterozygous for the gene sickle cell anaemia has a child but sadly the child dies from sickle cell anaemia. What genotypes and phenotypes must he and his wife have?

Sex Chromosomes XX XY XX X Y XX XY

Sex linked recessive inheritance Humans have 22 pairs of autosomes and 1 pair of sex chromosomes. In the females sex chromosomes are XX and in male they are XY. Sex linked genes are carried on the sex chromosomes (on the X chromosome as the Y chromosome is very small) e.g. colour blindness and haemophilia.

Parents: mother father P genotypes: X H X h X X H Y P phenotypes: Carrier female X Normal male Gametes: X H or X h X X H or Y F1: F1 Genotypes: 1 X H X H : 1 X H X h : 1 X H Y: 1 X h Y Phenotypes: 1 normal female, 1 carrier female, 1 normal male, 1 haemophiliac male X H X h X H X H X H X H X h Y X H Y X h Y

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Revision question 1.If a woman who was a carrier for colour blindness had children with a normal man, what was the chance of any girl they had being a carrier? 2.If a normal female had children with a colour blind male, what chance would there be of any of their sons suffering colour blindness?

Examine case studies of inherited conditions including single gene disorders, chromosome abnormalities and conditions influenced by multiple genes. Calculate probability of outcomes in single gene inherited conditions. Suitable examples include: albinism, Huntington’s chorea, sickle cell, thalassaemia, haemophilia, muscular dystrophy. Consider moral/ethical issues surrounding PGD. Draw, analyse and interpret pedigree charts over three generations to follow patterns of inheritance in genetic disorders using standardised human pedigree nomenclature and symbols (sex, matings, siblings, affected individuals, twins, heterozygotes, carrier of sex-linked allele and deceased).