Genetic screening Health Dictionary

The message set out sequentially along the human CHROMOSOMES. The human gene map is being constructed through the work of the international, collaborative HUMAN GENOME project; so far, only part of the code has been translated and this is the part that occurs in the GENES. Genes are responsible for the PROTEIN synthesis of the cell (see CELLS): they instruct the cell how to make a particular polypeptide chain for a particular protein.

Genes carry, in coded form, the detailed speci?cations for the thousands of kinds of protein molecules required by the cell for its existence, for its enzymes, for its repair work and for its reproduction. These proteins are synthesised from the 20 natural AMINO ACIDS, which are uniform throughout nature and which exist in the cell cytoplasm as part of the metabolic pool. The protein molecule consists of amino acids joined end to end to form long polypeptide chains. An average chain contains 100–300 amino acids. The sequence of bases in the nucleic acid chain of the gene corresponds in some fundamental way to the sequence of amino acids in the protein molecule, and hence it determines the structure of the particular protein. This is the genetic code. Deoxyribonucleic acid (see DNA) is the bearer of this genetic information.

DNA has a long backbone made up of repeating groups of phosphate and sugar deoxyribose. To this backbone, four bases are attached as side groups at regular intervals. These four bases are the four letters used to spell out the genetic message: they are adenine, thymine, guanine and cystosine. The molecule of the DNA is made up of two chains coiled round a common axis to form what is called a double helix. The two chains are held together by hydrogen bonds between pairs of bases. Since adenine only pairs with thymine, and guanine only with cystosine, the sequences of bases in one chain ?xes the sequence in the other. Several hundred bases would be contained in the length of DNA of a typical gene. If the message of the DNA-based sequences is a continuous succession of thymine, the RIBOSOME will link together a series of the amino acid, phenylalanine. If the base sequence is a succession of cytosine, the ribosome will link up a series of prolines. Thus, each amino acid has its own particular code of bases. In fact, each amino acid is coded by a word consisting of three adjacent bases. In addition to carrying genetic information, DNA is able to synthesise or replicate itself and so pass its information on to daughter cells.

All DNA is part of the chromosome and so remains con?ned to the nucleus of the cell (except in the mitochondrial DNA). Proteins are synthesised by the ribosomes which are in the cytoplasm. DNA achieves control over pro-tein production in the cytoplasm by directing the synthesis of ribonucleic acid (see RNA). Most of the DNA in a cell is inactive, otherwise the cell would synthesise simultaneously every protein that the individual was capable of forming. When part of the DNA structure becomes ‘active’, it acts as a template for the ribonucleic acid, which itself acts as a template for protein synthesis when it becomes attached to the ribosome.

Ribonucleic acid exists in three forms. First ‘messenger RNA’ carries the necessary ‘message’ for the synthesis of a speci?c protein, from the nucleus to the ribosome. Second, ‘transfer RNA’ collects the individual amino acids which exist in the cytoplasm as part of the metabolic pool and carries them to the ribosome. Third, there is RNA in the ribosome itself. RNA has a similar structure to DNA but the sugar is ribose instead of deoxyribose and uracil replaces the base thymine. Before the ribosome can produce the proteins, the amino acids must be lined up in the correct order on the messenger RNA template. This alignment is carried out by transfer RNA, of which there is a speci?c form for each individual amino acid. Transfer RNA can not only recognise its speci?c amino acid, but also identify the position it is required to occupy on the messenger RNA template. This is because each transfer RNA has its own sequence of bases and recognises its site on the messenger RNA by pairing bases with it. The ribosome then travels along the chain of messenger RNA and links the amino acids, which have thus been arranged in the requisite order, by peptide bonds and protein is released.

Proteins are important for two main reasons. First, all the enzymes of living cells are made of protein. One gene is responsible for one enzyme. Genes thus control all the biochemical processes of the body and are responsible for the inborn di?erence between human beings. Second, proteins also ful?l a structural role in the cell, so that genes controlling the synthesis of structural proteins are responsible for morphological di?erences between human beings.... genetic code

The procedure whereby advice is given about the risks of a genetic disorder and the various options that are open to the individual at risk. This may often involve establishing the diagnosis in the family, as this would be a prerequisite before giving any detailed advice. Risks can be calculated from simple Mendelian inheritance (see MENDELISM) in many genetic disorders. However, in many disorders with a genetic element, such as cleft lip or palate (see CLEFT PALATE), the risk of recurrence is obtained from population studies. Risks include not only the likelihood of having a child who is congenitally affected by a disorder, but also, for adults, that of being vulnerable to an adult-onset disease.

The options for individuals would include taking no action; modifying their behaviour; or taking some form of direct action. For those at risk of having an affected child, where prenatal diagnosis is available, this would involve either carrying on with reproduction regardless of risk; deciding not to have children; or deciding to go ahead to have children but opting for prenatal diagnosis. For an adult-onset disorder such as a predisposition to ovarian cancer, an individual may choose to take no action; to take preventive measures such as use of the oral contraceptive pill; to have screening of the ovaries with measures such as ultrasound; or to take direct action such as removing the ovaries to prevent ovarian cancer from occurring.

There are now regional genetics centres throughout the United Kingdom, and patients can be referred through their family doctor or specialists.... genetic counselling

Genetic engineering, or recombinant DNA technology, has only developed in the past decade or so; it is the process of changing the genetic material of a cell (see CELLS). GENES from one cell – for example, a human cell – can be inserted into another cell, usually a bacterium, and made to function. It is now possible to insert the gene responsible for the production of human INSULIN, human GROWTH HORMONE and INTERFERON from a human cell into a bacterium. Segments of DNA for insertion can be prepared by breaking long chains into smaller pieces by the use of restriction enzymes. The segments are then inserted into the affecting organism by using PLASMIDS and bacteriophages (see BACTERIOPHAGE). Plasmids are small packets of DNA that are found within bacteria and can be passed from one bacterium to another.

Already genetic engineering is contributing to easing the problems of diagnosis. DNA analysis and production of MONOCLONAL ANTIBODIES are other applications of genetic engineering. Genetic engineering has signi?cantly contributed to horticulture and agriculture with certain characteristics of one organism or variant of a species being transfected (a method of gene transfer) into another. This has given rise to higher-yield crops and to alteration in colouring and size in produce. Genetic engineering is also contributing to our knowledge of how human genes function, as these can be transfected into mice and other animals which can then act as models for genetic therapy. Studying the effects of inherited mutations derived from human DNA in these animal models is thus a very important and much faster way of learning about human disease.

Genetic engineering is a scienti?c procedure that could have profound implications for the human race. Manipulating heredity would be an unwelcome activity under the control of maverick scientists, politicians or others in positions of power.... genetic engineering

This technique shows the relationships between individuals: for example, it can be used to prove maternity or paternity of a child. The procedure is also used in FORENSIC MEDICINE whereby any tissue left behind by a criminal at the scene of a crime can be compared genetically with the tissue of a suspect. DNA, the genetic material in living cells, can be extracted from blood, semen and other body tissues. The technique, pioneered in Britain in 1984, is now widely used.... genetic fingerprinting

The use of procedures and measures to identify and differentiate apparently well persons who have a disease or condition or a high risk thereof from those who probably do not have the disease or condition.... screening

These are caused when there are mutations or other abnormalities which disrupt the code of a gene or set of GENES. These are divided into autosomal (one of the 44 CHROMOSOMES which are not sex-linked), dominant, autosomal recessive, sex-linked and polygenic disorders.

Dominant genes A dominant characteristic is an e?ect which is produced whenever a gene or gene defect is present. If a disease is due to a dominant gene, those affected are heterozygous – that is, they only carry a fault in the gene on one of the pair of chromosomes concerned. A?ected people married to normal individuals transmit the gene directly to one-half of the children, although this is a random event just like tossing a coin. HUNTINGTON’S CHOREA is due to the inheritance of a dominant gene, as is neuro?bromatosis (see VON RECKLINGHAUSEN’S DISEASE) and familial adenomatous POLYPOSIS of the COLON. ACHONDROPLASIA is an example of a disorder in which there is a high frequency of a new dominant mutation, for the majority of affected people have normal parents and siblings. However, the chances of the children of a parent with the condition being affected are one in two, as with any other dominant characteristic. Other diseases inherited as dominant characteristics include spherocytosis, haemorrhagic telangiectasia and adult polycystic kidney disease.

Recessive genes If a disease is due to a recessive gene, those affected must have the faulty gene on both copies of the chromosome pair (i.e. be homozygous). The possession of a single recessive gene does not result in overt disease, and the bearer usually carries this potentially unfavourable gene without knowing it. If that person marries another carrier of the same recessive gene, there is a one-in-four chance that their children will receive the gene in a double dose, and so have the disease. If an individual sufferer from a recessive disease marries an apparently normal person who is a heterozygous carrier of the same gene, one-half of the children will be affected and the other half will be carriers of the disease. The commonest of such recessive conditions in Britain is CYSTIC FIBROSIS, which affects about one child in 2,000. Approximately 5 per cent of the population carry a faulty copy of the gene. Most of the inborn errors of metabolism, such as PHENYLKETONURIA, GALACTOSAEMIA and congenital adrenal hyperplasia (see ADRENOGENITAL SYNDROME), are due to recessive genes.

There are characteristics which may be incompletely recessive – that is, neither completely dominant nor completely recessive – and the heterozygotus person, who bears the gene in a single dose, may have a slight defect whilst the homozygotus, with a double dose of the gene, has a severe illness. The sickle-cell trait is a result of the sickle-cell gene in single dose, and sickle-cell ANAEMIA is the consequence of a double dose.

Sex-linked genes If a condition is sex-linked, affected males are homozygous for the mutated gene as they carry it on their single X chromosome. The X chromosome carries many genes, while the Y chromosome bears few genes, if any, other than those determining masculinity. The genes on the X chromosome of the male are thus not matched by corresponding genes on the Y chromosome, so that there is no chance of the Y chromosome neutralising any recessive trait on the X chromosome. A recessive gene can therefore produce disease, since it will not be suppressed by the normal gene of the homologous chromosome. The same recessive gene on the X chromosome of the female will be suppressed by the normal gene on the other X chromosome. Such sex-linked conditions include HAEMOPHILIA, CHRISTMAS DISEASE, DUCHENNE MUSCULAR

DYSTROPHY (see also MUSCLES, DISORDERS OF – Myopathy) and nephrogenic DIABETES INSIPIDUS.

If the mother of an affected child has another male relative affected, she is a heterozygote carrier; half her sons will have the disease and half her daughters will be carriers. The sister of a haemophiliac thus has a 50 per cent chance of being a carrier. An affected male cannot transmit the gene to his son because the X chromosome of the son must come from the mother; all his daughters, however, will be carriers as the X chromosome for the father must be transmitted to all his daughters. Hence sex-linked recessive characteristics cannot be passed from father to son. Sporadic cases may be the result of a new mutation, in which case the mother is not the carrier and is not likely to have further affected children. It is probable that one-third of haemophiliacs arise as a result of fresh mutations, and these patients will be the ?rst in the families to be affected. Sometimes the carrier of a sex-linked recessive gene can be identi?ed. The sex-linked variety of retinitis pigmentosa (see EYE, DISORDERS OF) can often be detected by ophthalmoscopic examination.

A few rare disorders are due to dominant genes carried on the X chromosome. An example of such a condition is familial hypophosphataemia with vitamin-D-resistant RICKETS.

Polygenic inheritance In many inherited conditions, the disease is due to the combined action of several genes; the genetic element is then called multi-factorial or polygenic. In this situation there would be an increased incidence of the disease in the families concerned, but it will not follow the Mendelian (see MENDELISM; GENETIC CODE) ratio. The greater the number of independent genes involved in determining a certain disease, the more complicated will be the pattern of inheritance. Furthermore, many inherited disorders are the result of a combination of genetic and environmental in?uences. DIABETES MELLITUS is the most familiar of such multi-factorial inheritance. The predisposition to develop diabetes is an inherited characteristic, although the gene is not always able to express itself: this is called incomplete penetrance. Whether or not the individual with a genetic predisposition towards the disease actually develops diabetes will also depend on environmental factors. Diabetes is more common in the relatives of diabetic patients, and even more so amongst identical twins. Non-genetic factors which are important in precipitating overt disease are obesity, excessive intake of carbohydrate foods, and pregnancy.

SCHIZOPHRENIA is another example of the combined effects of genetic and environmental in?uences in precipitating disease. The risk of schizophrenia in a child, one of whose parents has the disease, is one in ten, but this ?gure is modi?ed by the early environment of the child.... genetic disorders

The screening of apparently healthy people to identify those who may have treatable diseases. Cervical smears are done when screening women to detect if they have cancer or precancer of the neck of the womb (cervix). Newborn babies are screened for hip dislocation. Screening tests are not designed to diagnose individual persons, but rather to divide a population into a large number at low risk and a small number at high risk of a condition. This allows clinicians to concentrate on a sub-section of the population. All screening tests produce false negative and false positive results, a problem often misunderstood by those at the receiving end. Factors to be assessed when planning screening procedures include the severity, frequency and distribution of the disease, and the availability and e?ectiveness of treatment. Convenience, safety, sensitivity and cost should also be assessed. In the United Kingdom the government has supported the extension of screening procedures for breast cancer, cervical cancer, hypertension and diabetes. (See PREVENTIVE MEDICINE.)... screening test

A set of investigations aimed at the early detection of breast cancer. It includes self-screening by monthly examination of the breasts, and formal programmes of screening by palpation and mammography in special clinics. In the UK the NHS o?ers regular mammography examinations to all women between 50 and 64 years of age; in 1995–6, 1.1 million women were screened – 76 per cent of those invited. More than 5,500 cancers were detected – 5.3 per 1,000 women screened.... breast screening

Tests to detect early signs of cancer in groups of people who are susceptible to cancer because of their age, occupation, lifestyle, or genetic predisposition. Tests for cancers of the cervix (see cervical smear test), breast (see mammography), bladder, and colon have proven to be effective.... cancer screening

A specific fragment of DNA that is used in laboratory tests to determine whether particular genetic defects are present in an individual’s DNA.

Genetic probes are mainly used in antenatal diagnosis of genetic disorders, and in investigating whether people with a family history of a genetic disorder carry the defective gene themselves.... genetic probe

Prenatal screening of fetal abnormalities may be the result of screening tests carried out on most or all pregnant women, or as the result of speci?c diagnostic tests performed to detect speci?c conditions. Prenatal diagnosis is important as it will identify babies who might need medical or surgical treatment before or soon after birth. In addition, it may also detect severe abnormalities for which parents might decide to have a therapeutic ABORTION.

ULTRASOUND scanning is probably the most widely used diagnostic tool in obstetric practice. It can detect structural abnormalities such as SPINA BIFIDA and CLEFT PALATE and even cardiac and renal problems. A series of scans can assess whether the baby is growing at a normal rate; ultrasound may also be used to assist with other diagnostic tests (e.g. AMNIOCENTESIS – see below).

Tests on the mother’s blood can also diagnose fetal abnormalities. Alphafetoprotein (AFP) is produced by babies and ‘leaks’ into the AMNIOTIC FLUID and is absorbed by the mother. In spina bi?da and other neural-tube defects there is increased leakage of AFP, and a blood test at 16 weeks’ gestation can detect a raised level which suggests the presence of these abnormalities.

The triple test, also performed at 16 weeks, measures AFP and two hormones – HUMAN CHORIONIC GONADOTROPHIN and unconjugated OESTRADIOL – and is used in diagnosing DOWN’S (DOWN) SYNDROME.

Amniocentesis involves inserting a needle through the mother’s abdominal wall into the uterus to remove a sample of amniotic ?uid at 16–18 weeks. Examination of the ?uid and the cells it contains is used in the diagnosis of Down’s syndrome and other inherited disorders. The test carries a small risk of miscarriage.

Chorionic villus sampling may be used to diagnose various inherited conditions. A small amount of tissue from the developing PLACENTA is removed for analysis: this test has the advantages of having a lower incidence of miscarriage than amniocentesis and is carried out at an earlier stage (9–13 weeks).

Analysis of a blood sample removed from the umbilical cord (cordocentesis) may diagnose infections in the uterus, blood disorders or inherited conditions.

Direct observation of the fetus via a viewing instrument called a fetoscope is also used diagnostically and will detect structural abnormalities.

Most tests have a recognised incidence of false positive and negative results and are therefore usually cross-checked with another test. Counselling of the parents about prenatal tests is important. This allows them to make an informed choice which may not necessarily involve terminating the pregnancy if an abnormality is found. (See PREGNANCY AND LABOUR.)... prenatal screening or diagnosis

*screening tests to detect the presence of precancerous changes in the cervix (neck) of the uterus (see cervical intraepithelial neoplasia). *Cervical smears are the standard first-line screening tools in most countries: screening programmes based on the traditional Papanicolaou (Pap) test have been mostly superseded by *liquid-based cytology. *Colposcopy is indicated when abnormal cells (*dyskaryosis) are detected.... cervical screening

a screening tool for young people under the age of 21 to identify alcohol and drug use. The first part consists of three questions about drug or alcohol use over the past year. Participants giving positive answers to two or more questions proceed to the second part (from which the name derives), which contains six questions with the key words car, relax, alone, family/friends, forget, trouble, used to assess the need for further input.... crafft screening test

the tendency for variations to occur in the genetic composition of small isolated inbreeding populations by chance. Such populations become genetically rather different from the original population from which they were derived.... genetic drift

see MUST.... malnutrition universal screening tool

*screening tests carried out on newborn babies to detect diseases that appear in the neonatal period, such as phenylketonuria (see Guthrie test). If these diseases are detected early enough, treatment may be instigated before any irreversible damage occurs to the baby.... neonatal screening

(PGD) a diagnostic procedure carried out on embryos at the earliest stage of development, before implantation in the uterus. Access to these early embryos requires the *in vitro fertilization of egg cells: three days after fertilization one or two cells are aspirated from the six-cell embryo; alternatively, tissue is removed from an embryo at five or six days, when it has reached the *blastocyst stage. Isolated cells can then be genetically analysed, allowing the transfer of selected embryos to the mother. One of the major applications of PGD is for the detection (using the *FISH technique) of chromosomal abnormalities, especially *aneuploidies (e.g. Down’s syndrome); the procedure is used mainly in women who have had repeated miscarriages or have failed to achieve pregnancy after several IVF treatment cycles, which could be due to the presence of such abnormalities in the embryo. PGD can also be used to detect defective genes responsible for hereditary disorders (e.g. the commonest form of cystic fibrosis, Huntington’s disease) and genes associated with susceptibility to certain cancers. When a defect is detected, *genetic counselling is offered.... preimplantation genetic diagnosis

*screening tests carried out to estimate the risk of chromosomal or other abnormalities being present in a developing fetus. They include blood tests to measure levels of *human chorionic gonadotrophin (hCG), *PAPP-A, *alpha-fetoprotein (AFP), inhibin (see activin), and *unconjugated oestriol (uE3) (see also triple test) and also ultrasound scanning for the presence of soft markers (see ultrasound marker; nuchal translucency scanning). If the results indicate a high risk of abnormalities being present, a diagnosis may be confirmed by more invasive procedures (see prenatal diagnosis).... prenatal screening

(NSC) the body responsible for advising the NHS, the ministers of the UK government, and the three devolved governments in the UK about all aspects of screening. The NSC also has responsibility for overseeing all noncancer screening programmes in the NHS in England and monitoring their quality and effectiveness. It was formed in 1996 and became part of *Public Health England in 2013. See screening test.

National Screening Committee website: contains detailed notes on all screening programmes the committee has considered and the rationale for the decisions the committee has made... uk national screening committee

the use of an image intensifier to produce *real-time imaging during an X-ray examination on a TV monitor. It is widely used in angiography and *interventional radiology to guide procedures. See videofluoroscopy.... x-ray screening