Origin of hereditary disorders

Our genetic heritage is contained in the genes or recipes inside the chromosomes. Chromosomes are not rigid structures, but totally the contrary; they are changeable and susceptible to mutation. This allows them to interact with the environment; being able to adapt due to their own evolution and reset mechanisms. Thus, any faulty or inappropriate changes affecting their number, structure, content or expression, can give rise to malformations or disorders.

Congenital disorders may be caused by any of the following alterations:

• Chromosomal: When the chromosome is altered in either the number or structure.
• Mendelian: When the alteration affects the chromosome contents or message, that is their genes or recipes.
• Mitochondrial: Our inheritance is not only in the chromosomes or nucleus DNA. A small amount of it is found in the mitochondria, a cellular structure located outside the nucleus, in a region called cytoplasm.
• Multifactorial: When the disorder or defect is the result of various genes acting together, plus the interaction of these genes with exogenous or environmental factors.
• Enviromental: Produced by an external cause that affects the individual.

Disorders can be diagnosed once we know what has caused them.
With a probable diagnosis, we must choose the most appropriate technique from all the techniques available, so our diagnosis can be demonstrated and confirmed and then proceed accordingly.

Advances in the field of human genetics are spectacular as a result of integrating the different molecular biology techniques. New hereditary phenomena are being constantly discovered that must be taken into account and which were unimaginable a few years ago, such as:

• The genomic imprinting: this concept refers to a gamete, be it an ovum or a spermatozoon, which, depending on whether it has undergone a male or a female meiosis, the same recipe or gene in some chromosomes may be activated or deactivated. In other words, in normal conditions, we express the recipe of a progenitor and if this process of activation or deactivation has taken place incorrectly it could lead to problems.
• Nucleotide expansion: in some disorders, the gene or pathological recipe loses its stability, and somewhere along its information chain, it can undergo a mechanism of expansion or repetition. This would be the same as a word that is repeated several times in the same line, as if the gene “stuttered” and its message was not understood. If the “stuttering” became worse, that is, the word began to repeat itself from generation to generation, making it very unstable, we would be able to see that in that particular family the disorder would maniffest more and more in an earlier and more severe form, phenomenon known as anticipation.
• Uniparental dysomy: this concept refers to the fact that the same chromosomal set, or part of it, derives from the same progenitor as a result of some sort of error during meiotic division.

Once the situation is totally clear, we proceed to employ the most appropriate diagnostic techniques in each individual case. Please note that some of these techniques can be applied either during the prenatal or the post-natal period, that is, before or after the child is born.

• Chromosomal disorders
• Mendelian or Mitochondrial disorders
• Multifactorial disease
• Environment-related disease

Chromosomal disorders

We must use TECHNIQUES for CHROMOSOME ANALYSES.

Let’s remember that the karyotype is the photography of all our sorted chromosomes, based on an international classification , from largest to smallest , setting aside the sex chromosomes.

We can establish the amount of chromosomes, their structure, whether they are missing or have any extra structures, and whether the information is in the right place or whether it has been transferred to another site.

 

Among the several techniques available, the most frequently used ones are those that are user friendly and low cost. Such techniques allow us to visualize all the chromosomes, in black and white, with a band pattern that permit us to identify each one separately at the same time. These techniques are known as cytogenetic techniques.

Other more newly developed techniques are the so called molecular cytogenetics techniques. There are several types based on their different utilities, being the use of color a common feature in all of them. These techniques include:

 

Techniques that allow us to observe all the chromosomes as in the previous photograph, but that have coloured bands instead of black and white ones. These techniques are known as multicolour banding techniques.

 

Another technique is comparative genomic hybridization (or CGH), which allows us to see if a chromosome is missing or exceeding a little bit based on the different color patterns that are formed and whose intensity is measured and interpreted by a computer program, compared to a reference sample. There are two varieties of the this technique: conventional CGH and array CGH.

• Wikipedia, Comparative genomic hybridization

 

Other techniques are used to visualize specific parts within a chromosome, and based on the region we are studying, the techiques are given names. For example: centromeric probes technique, locus specific probe technique, etc.

 

 

Other techniques are used to see each pair of chromosome in a different color, enabling us to visualize them all at once. This technique, known as SKY or multicolor FISH (Fluorescence In Situ English Hybridization), enables us to diagnose partial or total gains and losses of chromosomes through their color, as well as structural abnormalities involving several chromosomes. The piece that is repeated or unstructured will be of the same color as the chromosome to which it corresponds.

• Wikipedia, Hibridación fluorescente in situ

 

 

 

…or just visualise a specific set or sets. For example, in this case, we only want to visualise the pink chromosome.

 

As you can see these techniques make the study of chromosomes easier, mostly in cases of structural alterations. For example, in cases where a piece of chromosome attaches to a different set.

 

 

We can see it very clearly! Blue chromosome number 1 has a pink piece stuck to it. If this study is done in black and white we might not notice it, and sometimes it might be very difficult to diagnose.

 

 

The physician and the laboratory in charge of the case will decide jointly which techniques should be used. On some occasions, these tests are used as a diagnostic adjunct to conclude the diagnosis.

Another technique is QF-PCR (quantitative fluorescence polymerase chain reaction). This technique allows us, in the case of pregnant women, to rule out the most common chromosomal abnormalities involving chromosomes 13, 18, 21, X, Y. After obtaining cells from chorionic villi, amniotic fluid and fetal blood, without requiring the culture of these samples, the results are obtained after 24 to 72 hours.

• Hospital Universitario Central de Asturias, Biblioteca de Pruebas-Citogenética- Laboratorio de Medicina
• Técnica QF-PCR en Diagnóstico Prenatal y Postnatal
• Diagnóstico prenatal rápido de aberraciones cromosómicas por QF-PCR

Clearly, all these techniques should only be performed in highly specialized centers that require expensive IT support and highly qualified and trained staff for the evaluation and interpretation of these results.

The use of these or other techniques must be based on the doctor´s clinical judgement and the laboratory that is performing the tests, because sometimes these techniques are used as a complement to conclude a diagnosis. For example, in diseases caused by loss or gain of genetic material, very small- sized microalterations cannot be detected by means of standard cytogenetic techniques. All these techniques have their pros and cons, and should therefore be previously evaluated based on what they offer and what we are looking for: diagnostic possibilities, reliability, speed, cost, complementarity, etc.

Mendelian or Mitochondrial disorders

This means the information contained in the genes or recipes inside chromosomes in the nucleus, or the DNA in the mitochondria.

We will use BIOCHEMICAL or MOLECULAR TECHNIQUES for specific diagnosis of these disorders.

Some of these specific diagnostic tests are not available nowadays for some disorders.

There will be two possibilities if this is the case:

1. The individual is already born, so he will not have a diagnosis till a specific test is found.
   If it is a very serious sickness and the individual might die, a blood sample should be taken, which will be kept frozen for future use, together with a complete medical history, photographs and other specific additional tests. If at some time in the future the couple or other relatives would want to know if they might have more children with the same disorder, and if a specific test is by that time available, the stored blood sample will be used to establish the diagnosis. There is no other option available at this moment.
2. Or, if on the contrary, the individual has not been born yet, that is during the prenatal period.
   If the presenting disorder or pathology is accompanied by some sort of malformation that can be diagnosed through an ultrasound examination, we will use this latter technique to indirectly monitor the anatomy of the baby’s via ultrasound.

Multifactorial disease

That is, there are several factors contributing to its aetiology, both of a genetic (predisposing factors) and environmental nature, the different tests available will be applied in an attempt to establish the origin of the disease, conclude the diagnosis, and at the same, assess the risk as well as the different preventive options available, should a future pregnancy occur.

Environment-related disease

The triggering agent has to be identified and the appropriate measures taken to eliminate it or to avoid it.

Related questions

What is genetic counselling?

Genetic counselling is an information process whereby a geneticist, a specialist in human genetics, informs an individual, couple or group of individuals, of the diagnosis, prognosis, treatment, risk and ways to prevent a given disease.
This consultation should only be performed by professionals who have great sensitivity, a sense of humanity, and a good ability to communicate. An easy to understand, clear and concise type of language should always be used, while adopting at all times a non-directive approach.

Upon completion of the informative session, the patients or consulting party, after having understood all the information, should be capable of freely making up their own minds based on their wishes and convictions. If this aim is not achieved, then the professional in charge of the counselling session will have failed in his or her mission.

¿Where should we go to find out whether or not a malformation or disease is hereditary?

Medical advice should be sought from a physician who specialises in human genetics. This specialist can be found in large hospitals with a genetics department, or alternatively in private practices.

What members of the family should be studied when a balanced structural chromosomal alteration is diagnosed in an individual?

It would depend on who the affected individual is. Let´s see:

• Parents with an affected child
  If the parents of the affected child are the ones seeking medical advice they should be the first to be screened. If either of the parents is a carrier of the same chromosomal alteration, it can be transmitted to other children they may have in the future. This transmission can occur in a balanced or unbalanced manner based on how the chromosomes were divided during meiosis.
• Affected individual
  If the affected individual has any siblings or children, it is advisable for them to be screened also so that any possibility of them being carriers of the same chromosomal alteration is ruled out. This would enable to perform an adequate reproductive assessment in all the cases to prevent malformations with a view to future pregnancies.

If the number of siblings is high, it is easier to start with the parents if they are still alive. If one of the parents has the same chromosomal alteration, it is possible for any of the other affected invididual´s siblings to have inherited the same chromosomal alteration.

In contrast, if neither of the parents has the alteration, the possibility of these to have more children with the same alteration is very low because most likely it is a novo mutation . However, it is not always possible to rule out a gonadal mosaic or a false paternity for that matter.

If both parents are dead, or if one of them has died but the one who remains alive is normal, given that it is impossible to determine the cariotype of the deceased parent, the siblings of the affected individual who is carrying the chromosomal alteration should all be screened to make sure that they are not carriers.

If the individual affected with the condition is a man or woman of reproductive age, it is advisable to carry out a chromosomal study of the fetus in each pregnancy under the care of their geneticist or obstetrician.

How can we find other people with the same problem?

Other people in the same situation can be found through your geneticist, department of genetics, searching the Net, local associations, or by attending support groups, hospitals, or by writing to the World Health Organisation.

You can also browse in Links of interest on our website, and have a look to our forum.

Which tests should be performed for genetic counselling purposes in an individual who has died or could die without an specific diagnosis?

Although an specific diagnosis may not be available, probably there is some orientation pointing to a diagnosis, and thus, besides keeping a record of all the specific studies performed on the individual, it would be appropriate to gather the following information should it be required in the future:

• Complete radiological study.
• Complete medical history.
• Complete photographic documentation, mainly in cases of malformation or syndromes (it is easier to see than to describe).
• Blood sample or frozen tissue sample, should it be required in the future to either conclude or confirm a diagnosis, among them molecular biology studies (DNA).
• Chromosomal study.

And when the individual in question dies:

EPathological anatomy study (autopsy). As science keeps making advances, new techniques keep developing in this specific field. Among these techniques, the application of postmortem imaging techniques such as NUCLEAR MAGNETIC RESONANCE IMAGING (MRI), may be useful in cases of specific malformations, especially brain malformations, which may be difficult to confirm for technical reasons using traditional autopsy techniques.
This technique generates an archive of staged images of the organ under study that will prove useful for subsequent assessment, and at the same time makes it possible to take biopsies from specific sites, which may in future avoid the need to perform a full autopsy.

If you require further information on this subject, please contact Dr Neil Sebire by email, Consultant Paediatric Pathologist, Great Ormond Street Hospital, London.

Why do hereditary disorders occur?

Hereditary disorders occur because our DNA undergoes changes and some of these changes are pathological.

These changes are caused by the constant pressures DNA is subjected to in its non-stop struggle to adapt to the environment in which we develop.

Moreover, these are changes that occur at random, and given that we have no control over them, because they “simply” take place inside our body, no one should feel bad or guilty about it. All we can do is to diagnose the condition, and where possible, to apply the appropriate measures for primary prevention in order to avoid a recurrence.

Can the same hereditary disorder be inherited in different modes?

Yes, the same disorder can present different patterns of inheritance. This is why it is so important to elaborate a genealogic tree that will permit to find out how the gene is expressed or secreted in the family and to know the type of heredity it corresponds to.

And, how is this possible?

Because the same disease can be caused by different genes with different heredity patterns.

An example of this would be a person that has a “headache”. The pain can be of the same intensity and be localized in the same area, but some people will have the pain as a result of a head bang, trauma, a migraine, a tumor, a visual defect that has not been corrected with appropriate lenses, a cold…. and an endless list of reasons that trigger the pain.

This is why, when dealing with a hereditary disorder, the affected individual should seek medical advice with a specialist in human genetics who will assess the condition and provide personalized genetic counselling.

Can we choose the gender of our children?

The answer is yes, you can. However, in most countries this technique cannot be used just to please the parents. It can only be used when there is a strong medical reason to select a gender.

Next topic: How can all this knowledge be used to our benefit?