Site author Richard Steane
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Identification and diagnosis of heritable conditions

Heritable conditions

There are a large number of conditions that can be passed on from generation to generation, so they are described as heritable. Nowadays these are often not referred to as inherited diseases, as the term may be thought to imply some sort of allocation of blame on or from previous generations. They may also be known as 'inborn errors of metabolism'. Unlike communicable diseases, they may not be be avoidable or treatable with simple (?) medicines, and they are certainly not 'curable'. Sometimes these conditions are said to 'run in the family' so that medics are prepared to check newborn babies for these conditions if there is a clear medical history, perhaps in the wider family.

The basis of this heritability is obviously part of the genetic makeup of individuals concerned, and there are specific alleles involved in most cases, although there are often a number of different versions. Clearly these result from changes in the base sequence responsible for some aspect of the body's chemistry, and these alleles are passed on in ways that are reflected in genetic examples already studied.

And changes in base sequence may result from mutation, so sometimes these conditions may appear to arise 'out of the blue'.

The blood spot test, given to all babies at the age of five days, screens for 9 rare but serious inherited conditions:
  1. Sickle cell anaemia - defects in the protein haemoglobin affecting oxygen carriage and packing into red cells
  2. Cystic fibrosis - defects in the fibrosis transmembrane conductance protein which forms channels on the cell surface to allow the movement of chloride ions in and out of the cell - especially in the lungs but with major effects on other organs too.
  3. Congenital hypothyroidism - caused by insufficient thyroxine production by the thyroid glands

  4. The conditions above are found in about 1 in every 2000-3000 babies.
    There are also a number of conditions below caused by problems metabolising normal body chemicals, such as specific amino acids

  5. phenylketonuria (PKU) (See alongside)
  6. medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
  7. maple syrup urine disease (MSUD)
  8. isovaleric acidaemia (IVA)
  9. glutaric aciduria type 1 (GA1)
  10. homocystinuria (pyridoxine unresponsive) (HCU)

Examples of heritable conditions

Phenylketonuria is a prime example of an inherited condition that can be easily identified and treated if it is identified early enough..

Phenylketonuria (PKU) is caused by a mutation in the gene responsible for the enzyme phenylalanine hydroxylase (PAH). The enzyme normally causes the conversion of the amino acid phenylalanine (Phe) - a so-called 'essential' amino acid - to the amino acid tyrosine (Tyr). In fact more than 400 disease-causing mutations have been found in the PAH gene. Similar symptoms result from a rare condition - deficiency of the coenzyme tetrahydrobiopterin, which is necessary for proper activity of the enzyme PAH.

Consequently there may be a buildup of phenylalanine in the blood, as well as a deficiency of tyrosine, and over time it can cause mental retardation, and other problems such as seizures. When a baby is in the womb, the mother's blood system removes the excess phenylalanine but after birth its accumulation can be detected as a result of screening tests such as the 'heel prick' test. Blood sampled in this way is subjected to a fairly low-tech chemical test and those affected are put on a low protein ('PHE-restricted') diet for life. Unfortunately this includes the avoidance of a large variety of canned drinks containing the artificial sweetener aspartame - which is flagged on the contents list.

It is said that PKU is an autosomal recessive genetic disorder, and it affects about 1 in 12,000 babies.

What does autosomal mean?
> It is carried on/its locus is on a non-sex chromosome - chromosomes 1-22, not X (or Y).
      In fact it is actually on chromosome 12.

> It is not 'sex-linked , i.e. not more likely in males than females
What are the consequences of it being recessive?
> Two copies of the allele must be present if it is expressed
> These are likely to come from each parent
> And they are likely to be 'carriers' i.e. heterozygotes, not affected themselves.

Differences in DNA can be exploited for identification and diagnosis of heritable conditions

Although the major heritable conditions are often confirmed by fairly simple chemical tests, more technical tests can be performed by comparing patients' DNA sequences with reference samples. And samples can be almost simultaneously checked for a number of different conditions.

Furthermore, analysis of the details of genetic traits can signal different treatment options. See below

The same sequence comparison techniques may be used to identify different strains of pathogenic bacteria and viruses.

DNA probes and hybridisation

DNA probes are sections of single-stranded DNA that have a base/nucleotide sequence which is complementary to sections of DNA of interest, such as particular alleles, or DNA fragments obtained after treatment with restriction enzymes.

These probes may be chemically labelled with a dye that gives a distinctive colour, or a fluorescent pigment that emits light of a certain wavelength when illuminated with ultraviolet light, the intensity of which can be measured, or they may even be radioactively labelled.

Different probes can be of different sizes (lengths) so they may be separated and identified following gel electrophoresis, and shorter fragments move further in a given time.

In order to use DNA probes in identifying specific matching DNA in a sample, it is necessary to convert the sample DNA into single stranded form.

It is normal to strongly heat the sample (to over 86 °C) so as to separate the two strands. This is part of the polymerase chain reaction (PCR) procedure - 'denaturation' - and the probes effectively function as templates. At a slightly lower temperature, the DNA probes will bind to one of the DNA strands with the complementary base sequence. This is called DNA hybridisation - or 'annealing' in PCR.

DNA probes can be synthesised to ensure they have a specified base/nucleotide sequence, or they can be removed from a cell and amplified using PCR and then 'cut to size' using restriction enzymes.

Sometimes DNA probes start out as short sections of (labelled) double-stranded DNA.
They may then become single stranded as they are heated with double stranded target DNA, and then hybridise with one (or both?) target strands, allowing identification by means of the labelling.
See the FISH graphic below

Fluorescence In Situ Hybridization (FISH)

FISH (78K)
A mystery - what do the pink sections show?
Similarly, labelled DNA probes may be heated with cells undergoing division and then transferred to microscope slides, where the resulting fluorescent or coloured sections of chromosomes can be used to identify the locations of genes.
A shining example of DNA Hybridisation FISHprocess (61K)

Screening patients for heritable conditions

In adults, DNA may be obtained from blood samples, buccal cells and even hair follicles and urine.

Carrier screening

Potential parents may be aware of genetic conditions that have affected some of their relatives.
In fact in some cultures or ethnic groups it is considered essential for couples to undergo genetic testing for certain 'faulty genes' before proceeding to marriage.

In African and Caribbean populations Sickle Cell disease is an issue; homozygotes suffer from full-blown sickle cell anaemia, although heterozygotes may just show sickle cell trait.

Thalassemia is another genetic disorder affecting the blood. It is more common in people of African and Mediterranean descent.

Tay-Sachs disease occurs with greater frequency among Jewish people of Ashkenazi descent, i.e. those of Eastern or Central European descent. It affects the development of the nervous sytem, often with fatal consequences in early life.

Potential parents who are carriers are often aware of the possible ill-effects of their offspring inheriting one of these faulty alleles and turning out to be heterozygous like them. Two heterozygotes can expect three alternative outcomes if they have children: 50% chance of being heterozygous like them, or 25% chance of being doubly homozygous for the condition, or 25% chance of being doubly homozygous and unaffected by the condition.

Dominant alleles

Some conditions caused by dominant alleles sometimes do not show their effects until later in life; people carrying (only one of) these alleles are able to have children, and the chance of passing on the condition is 50%. Genetic testing of potential parents and offspring can provide information about the alleles involved, before they have had a chance to develop the characteristic symptoms of the condition.

Prenatal diagnostic testing

This is used to discover which alleles have been passed on to the developing foetus. This type of testing is offered to couples with an increased risk of having a baby with a genetic or chromosomal disorder.

Tissue samples for testing can be obtained through amniocentesis or chorionic villus sampling. Both of these procedures carry a certain risk of causing miscarriages, but a much safer technique, ' non-invasive pregnancy screening', involves removal of a blood sample from the mother and testing it for 'cell-free' foetal DNA, traces of which pass from foetal to maternal blood.

Pre implantation screening

If a couple who are both carriers for a recessive genetic condition want to have children, they may decide to proceed with in-vitro fertilisation. In this case, usually several eggs are removed from the woman and fertilised in the laboratory using the man's sperms, and the resulting embryos can be checked by DNA before implantation into the woman's uterus.
It is likely that only unaffected embryos will be implanted.

Genetic counselling and personalised medicine

Using DNA probes to identify heritable conditions may have ethical implications.
They may confirm degenerative conditions that have yet to develop, e.g. Huntington disease.
They may also be used to screen for carriers for certain conditions.
Obviously in these situations reasons for testing and interpretation of results need to be tactfully explained.


Pharmacogenomics is the study of the role of the genome in drug response.

In some cases there are different treatment options depending on the details of the conditions themselves.
For example, some forms of cystic fibrosis can be treated with drugs that stabilise the CFTR channel protein, or cause it to open and restore some of the normal functions. These drugs are not effective in all cases and obviously genetic screening can ensure that they are only used when appropriate.

Certain medications used to treat some medical conditions are broken down and removed from the body by enzyme action; if these enzymes are inactive because of a genetic mutation the buildup of these medications can have life-threatening consequences. DNA profiling may identify patients with this condition, and alternative treatments may be initiated.

Identifying CF

About 1800 different alleles for cystic fibrosis have been identified, all producing a slightly different CFTR protein which does not function in the same way as the protein product of the normal allele.

It has been found that 23 mutations account for 94% of detectable mutations, and these can be detected by multiplex polymerase chain reaction (PCR)-based hybridization (with mutation-specific oligonucleotide probes).

The most common CF mutation, F508del, is the deletion of a single codon, resulting in the loss of one amino acid (phenylalanine) from the polypeptide chain making the CFTR protein. This changes the shape of the CFTR protein, which prevents its function allowing the passage of chloride ions through cell membranes.

The drug Orkambi (lumacaftor/ivacaftor) causes CFTR protein with an F508del mutation to fold into a more correct shape, and then activates the protein to allow more chloride to pass through.
It should not be used with different forms of cystic fibrosis caused by other alleles .

Other related topics on this site

(also accessible from the drop-down menu above)

Gene expression
Recombinant DNA technology - see PCR

Web references

Phenylketonuria (PKU) - LibreText, supported by the Department of Education Open Textbook Pilot Project, and the California State University Affordable Learning Solutions Program - content licensed by CC BY-NC-SA 3.0.

Newborn blood spot test - from the NHS

Blog PHE Screening Newborn blood spot screening turns 50

Cystic Fibrosis Foundation - very good explanation of a number of issues - but you may need to add your own knowledge of scientific terminology

Types of CFTR Mutations

F508del Mutation Testing

Sample Processing and DNA Extraction: Extracting DNA from Blood - interesting video about quality control of DNA destined for screening procedures

Fluorescence In Situ Hybridization (FISH)

Fluorescence in Situ Hybridization from Cell Line Genetics - Thanks for the picture of labelled chromosomes

Semrock - 'the standard in optical filters for the life science industry' - Thanks for the graphic

The Human Fertilisation and Embryology Authority

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