A partner in the clinical negligence department, Anne Winyard, and her team have dealt with a number of compensation claims for clinical negligence following “missed”
genetic diagnosis of a family-specific
inherited disease.
Genetic tests are sometimes performed on adults and children, and occasionally they are done during pregnancy to see if a fetus is affected. The test may be carried out to look for the presence of a disease, or it may be to see if the person being tested is a ‘carrier’; that is, they do not have the disease, but might be able to pass the disease to their children.
An accurate
genetic diagnosis of an inherited (familial) disease, despite the support of properly trained counsellors, can be devastating for a family. But a ‘missed’ (or inaccurate) diagnosis can often have worse consequences.
Anne’s team is experienced in investigating and pursuing claims involving
genetic diseases, and has previously obtained compensation for clients whose
genetic testing has been either wrongly carried out or wrongly reported.
Some further information about genetic testing is given below.
If you think you may have grounds for a claim, or would like to discuss your particular circumstances following your own genetic testing, or that of a member of your immediate family, then please e-mail
postbox@leighday.co.uk, or telephone 020 7650 1200, stating you are enquiring about a potential claim for clinical negligence.
DNA – the book of life
Genetic testing/diagnosis is carried out on
Deoxyribo
Nucleic
Acid (“DNA”).
Almost every cell in the human body contains genomic DNA, sometimes known as ‘the Book of Life’. Genomic DNA - DNA from the human genome - contains almost all of the genes that are required for life. The remaining genes are encoded in the DNA of mitochondria (small, sub-cellular units that are the powerhouse for each cell). Mitochondrial DNA is also known to be the cause of some inherited diseases.
Human genomic DNA is arranged in ‘chapters’, known as chromosomes. There are 23 pairs of chromosomes. Normally, all chromosomes are in duplicate (giving a total of 46 chromosomes). Generally, each of us inherits one copy of each chromosome from each of our parents.
Each one of a pair is generally the same size as the other with the exception of the sex chromosomes (described below). The pairs vary in size and the first 22 pairs (called autosomes) are numbered from the largest (pair number 1) to the smallest (pair number 22). The remaining pair (X and Y) are known as the ‘sex chromosomes’. They differ in length, and in the number of genes they carry. Generally, females have two X chromosomes (46 XX in genetic shorthand) and males have one X and one Y chromosome (46 XY in genetic shorthand).
There are only 4 ‘letters’ in the book’s alphabet. These ‘letters’ (representing DNA ‘bases’, or ‘nucleotides’) are known for short by their initial letters, as A, C, G and T. The ‘letters’ combine to make the ‘words’, i.e. genes. Each ‘word’ or gene has a functional role, necessary for life – for example instructions telling the body how to manufacture a particular protein.
Each ‘gene is ‘spelled out’ (‘coded’ is the word geneticists use) by a specific sequence of hundreds or maybe thousands or more of bases. Different sequences of the 4 bases code for different genes. A small change in the bases in the DNA sequence can lead to abnormal function and give rise to
genetic disease.
Genetic testing is available for many genes known to be the cause of
inherited diseases. The majority of inherited diseases are the result of a
single difference in the genetic code of a gene; that is a single ‘wrong’, ‘missing’ or ‘extra’ base. For example, the gene encoding Fibroblast Growth Factor Receptor 3 contains 3,829 bases – all in a particular sequence. But if base (nucleotide) number 1,138 in this long gene is the nucleotide ‘A’ instead of the nucleotide ‘G’, the result - in this example - will be a specific disease, called Achondroplasia (which, amongst other effects, leads to short stature). Further examples of this type of disease include Tuberous Sclerosis, Cystic Fibrosis, Hereditary Non Polyposis Colon Cancer and familial breast/ovarian cancer.
Disease–causing changes in the genetic code can also include multiple ‘wrong’, ‘missing’ or ‘extra’ bases.
A very large percentage of the bases in the genome combine to make ‘words’ that are gobbledegook. These gobbledegook words in the genome are effectively ‘padding’ between, and within, the smaller number of meaningful ‘words’ or genes. Because these large areas of padding in our DNA do not determine our body chemistry and characteristics, changes can occur in individual sequences that are not harmful to the person’s health and get passed on to their children with no ill effect. So there are no convergent evolutionary pressures upon them over time and across populations. Accordingly, these changes, which occur in each generation, result in the padding sequences in each persons DNA (if you look at enough of them) being unique to that individual. For this reason they are often the parts of the DNA which are examined forensically – e.g. in paternity testing or police investigations - for the purposes of genetic ‘fingerprinting’.
Inherited characteristics
Normally, you inherit two genes for each characteristic; one from each parent; carried on the ‘chapter’ or chromosome, which that parent has passed on to you.
There are a number of different ways in which genetic conditions can be inherited. For example, some genes are 'dominant'. This means that if you inherit the gene for that characteristic from
either parent, then you will definitely have that characteristic. The gene for brown eyes is a dominant gene.
Other genes are 'recessive' – in order to show the characteristic you have to inherit the gene for it from
both your parents. The gene for blue eyes is a recessive gene. So if two brown-eyed parents have a blue-eyed child, the parents both have (recessive) blue-eye genes. Each parent has brown eyes, because in each case, the (recessive) blue-eye gene was ‘trumped’ by the (dominant) brown-eye gene.
The genes you carry are called your 'genotype'. The characteristics you show as a result are called your 'phenotype'.
So in the example above, the parents each have a brown-eye/blue-eye genotype, but a brown-eye phenotype; because the dominant brown-eye gene ‘trumps’ the recessive blue-eye gene. You cannot tell by looking at the brown-eyed parent (the phenotype) what that person’s underlying genotype is. In fact each parent in this example is, so to speak, a silent ‘carrier’ of a blue-eye gene.
There are a number of other ways in which genetic conditions can be inherited. One is called ‘translocation’, another ‘duplication’ and yet another is an unstable type of mutation called ‘dynamic or expansion mutation’.
Translocation
A few of us have one or more of our DNA words (genes) in the ‘wrong’ chapter of our DNA ‘book’. So one chromosome (‘chapter’) has too many ‘words’ (genes) and one chapter has too few. Such a person is called a ‘balanced translocation carrier’. That person has all the necessary genetic material (DNA) – albeit not in the ‘normal’ place – so, in most cases, will not themselves be adversely affected. But that person’s children may be adversely affected. If the parent, who is a ‘balanced translocation carrier’, passes on to their child either the chromosome with the missing gene(s) but not the chromosome with the extra gene(s) - or vice versa - the child will either have a bit missing from their genome or an extra amount of genetic material and, as a result, may either have abnormalities or die in utero.
Duplication
On occasions a whole chromosome is duplicated, resulting in 3 copies of that chromosome. The most well known example of this abnormality is Down Syndrome, where the most common genetic error is the presence of three copies of Chromosome 21 (also called trisomy 21).
Dynamic or expansion mutation
Some inherited diseases, in particular where there is an increase in severity of a disease or earlier onset of a disease over several generations, are caused by a type of mutation called dynamic or expansion mutations. These mutations are not a simple exchange of one ‘letter’ (base or nucleotide) of the 4-letter genetic alphabet for another, but an increase in the number of a disease-specific triplet of nucleotides, known as a trinucleotide repeat sequence (for example, CGG and CAG).
The carrier parent, who is not, generally, adversely affected, has an unstable area (containing a number of copies of the trinucleotide repeat sequence) within a particular gene, on a particular chromosome. If the child inherits the chromosome with the unstable area, that unstable area can expand, generating extra repeats of the three-letter sequence. There is a 50% chance that each child of that parent will inherit the chromosome with the unstable area.
If the number of trinucleotide repeats within a gene is too large, it can trigger a problem that results in an identifiable disease. For example, Fragile X syndrome is caused by an increase, above a critical number, of the triplet bases ‘CAG’ within a specific gene on the X chromosome. This expansion can lead to moderate/ severe learning difficulties and other problems.
Other examples of diseases caused by this type of trinucleotide repeat mutation include Huntington disease (previously known as Huntington Chorea), Friedreich’s Ataxia, Spinocerebellar Ataxia, Myotonic Dystrophy, Spinobulbar Muscular Atrophy and Dentatorubral-Pallidoluysian Atrophy (DRPLA).
Genetic testing
The main function of
genetic testing, or
genetic diagnosis, is to investigate
inherited diseases within families by looking to see whether an individual carries a copy of a specific gene containing a disease-causing mutation.
Genetic tests can be carried out on samples of blood, saliva, semen, biopsy material etc, depending on the gene under investigation.
If the genetic testing is positive for a particular mutation, then that disease-causing mutation will almost certainly be the reason why the individual suffers from (or will go on to suffer from) that particular disease/condition. Where an identified mutated gene is the reason why a disease runs in a family, then the gene can be looked for in other members of the family. This can be done both ‘horizontally’ (siblings, cousins etc) and ‘vertically’ (parents, grandparents etc) to see if other family members have, and are likely to pass on, the disease-causing mutation.
Genetic testing also enables a pregnant woman to have her unborn child tested for a disease-causing mutation. If the testing indicates the unborn baby will have the inherited disease, this allows her to make an informed decision as to whether or not to continue with the pregnancy.
Genetic testing also has the potential to allow a couple who would like to have a baby but know in advance that one or both of them carry a disease-causing mutation, to have Pre-implantation Genetic Diagnosis (‘PGD’). This is really IVF (‘In Vitro Fertilisation’ – of mother’s egg with father’s sperm) but with the added step of carrying out genetic testing on the resulting embryo (at the stage where the embryo contains only a few cells)
before implantation into the mother’s womb.
Such pre-implantation testing allows selection and implantation of an embryo which does not carry the mutated (disease-causing) gene.
Genetic misdiagnosis?
Each of the families for whom we act, or have acted, have a family specific inherited disease. This does not mean that every member of the family has the disease, but that an inherited disease affects some members of the extended family, as it is passed down through the generations.
For each of the families, the ‘index person’ had undergone genetic testing for a gene suspected of being the cause of their family specific disease. The original test result was reported as negative, and the index person tested was told that they and/or their children would be free of the
inherited disease.
Subsequently, sometimes many years later, after the index person had gone on to have children, doubt was raised about the original testing. This doubt may have been raised because of a review within the laboratory where the original testing was carried out, or because the index person has gone on to show symptoms of the disease. Sadly, retesting of the index person, or testing on some of their children, sometimes shows that the original testing, and therefore diagnosis, was incorrect; the index person did carry the disease-causing imitation and sometimes a child does so too.
Genetic Testing Techniques
Some of these errors may have occurred as far back as the 1980s. During the intervening period scientific advances have meant that disease specific gene testing has become more accurate. In the early years of
genetic diagnosis, genetic testing involved the use of a technique called ‘linkage analysis’, where a statistical analysis was used to estimate the probability that a person carried a specific disease-causing gene.
Then, thanks to advances in molecular genetics, a test known as ‘Southern Blot’ superseded linkage analysis, where available. Southern Blot analysis is a technique which involves using a small piece of DNA (called a probe) from a gene known to cause a specific disease, to investigate the full genetic code of a person suspected of carrying that gene.
Subsequent advances led to a new technique, called
polymerase chain reaction (PCR) analysis. This technique uses the index person’s genetic code as a template to make thousands of copies of the specific part of a gene known to contain a disease-causing mutation. This degree of replication means that the DNA of the mutant gene, if present and amplified, can be visualised.
If you think you may have grounds for a claim, or would like to discuss your particular circumstances following your own genetic testing, or that of a member of your immediate family, then please e-mail
postbox@leighday.co.uk, or telephone 020 7650 1200, stating you are enquiring about a potential claim for clinical negligence.
Information was correct at time of publishing. See terms and conditions for further details.