The genetics of DMD/BMD

DMD is the largest known human gene. Mapping and molecular genetic studies show that both DMD and BMD are the result of mutations in the large DMD gene, which is responsible for encoding the protein ‘Dystrophin’. The mutations are mostly (approximately two-thirds in both forms) deletions of one or many exons in the dystrophin gene. Around 65% of DMD and 85% of BMD males have a deletion within their DMD gene. Although there is no distinct relationship found between the extent of the deletion and the degree of severity of the disorder, DMD deletions usually give rise to ‘frameshift’. Frameshift is a condition where mutation results in a change in translational reading frames that allow the production of single protein from one or several overlapping genes.

Duplication of the gene can also give rise to abnormal dystrophin molecules; however, it is much rarer form of mutation in the DMD gene. Approximately 5-10% of affected patients have duplication within their gene.

Where is the DMD gene located?

Cytogenetic location of DMD gene is on Xp21.2. This means that the gene is located on the short (p) arm of the X chromosome at position 21.2.

The exact molecular location of the gene on the X chromosome is from base pair 31,047,265 to base pair33,267,646.

 Taken from: https://ghr.nlm.nih.gov/dynamicImages/chromomap/dmd.jpeg

How is it inherited?

The disorder is inherited as an X-linked recessive trait. In other words, DMD/BMD is caused by an X-linked gene. This means that the gene is located on the X-chromosome. Since, girls have two copies of X-chromosomes, if one X-chromosome has the faulty gene, the second X-chromosome will have a functional copy of the gene to compensate. The disorder is recessive which means that the individual will be normal, as long as they carry a functional copy of the gene, even if they also carry the faulty gene.

Therefore, since boys have an X and a Y chromosome (c.f. XX females), and because they only have one X chromosome (do not have another X chromosome to compensate for the faulty gene), they will develop DMD/BMD symptoms if they receive the defective gene from their mother. As a result of this, only boys are affected but their mothers may be carriers. Girls can also be affected; only if they carry two copies of the defective gene on their X-chromosomes i.e. both of their X-chromosome have the faulty gene. This condition is very rare.

Bear in mind that nowadays almost half of all affected boys have the disorder as a result of a spontaneous ‘mutation’ or change in the gene in the boy himself and no other member of the family carries it. This is, however, difficult to prove and can be determined only by careful assessment of the family and assessing the family history.

It is fairly common, when the mother carries the defective gene but is usually not herself affected by it. These mothers are known as ‘carriers’. A small number of female carriers manifest a mild level of muscle weakness themselves and are then known as ‘manifesting carriers’.
The chance of each subsequent son of a carrier mother to be affected is 50:50, and each daughter to be a carrier herself is 50:50.

After the diagnosis of an affected boy with the disorder, it is vital to seek genetic advice/counselling and carry out appropriate tests for those family members who are at risk of being carriers. This can help to stop passing on the disorder to the subsequent generations.

There are also unusual patterns of inheritance of this disorder (which are very rare) such as ‘gonadal mosaicism’ and ‘somatic mosaicism’.

How is the disorder diagnosed?

Once somebody has recognised that a child’s problems might be due to this disorder, there are reliable tests available which can be carried out in most hospital laboratories. An example of such tests is measuring blood levels of an enzyme called creatine kinase in affected boys who usually find out to have a very high concentration of this enzyme in their blood.

However, since there are other rare factors that may also result in high levels of creatine kinase in blood, for a specific diagnosis in families with no previous affected member, other tests are provided. The alternative tests can be genetic testing which looks for the actual fault in the dystrophin gene, and a muscle biopsy (studying the dystophin protein).

There are different DNA tests offered to the patients such as diagnostic testing, carrier testing and prenatal testing. The muscle-specific isoform of the dystrophin gene is consisted of 79 exons (specific sequences of DNA which play a vital role in production of proteins). DNA testing and analysis can usually detect and identify the specific type of mutation of the exon or exons which are affected. 

However, like any other molecular genetic tests, the diagnostic tests are not 100% accurate. DMD can be detected with about 95% accuracy by genetic studies performed during pregnancy.

Diagnostic testing

Multiplex ligation-dependent probe amplification (MLPA) assay is one of the most common tests which examines copy number changes in each exon (different section within a gene) of the DMD gene.

The advantage of MLPA assay testing is that it is able to detect all whole exon deletions and duplications.

Around 5-10% of boys with BMD, and 25-35% of boys with DMD, do not have whole exon deletions/duplications and instead may have other types of mutation such as small insertions, deletions, point mutations, etc. The main disadvantage of MLPA testing is that, aside from whole exon deletions/duplications, it is unable to detect other forms of change in the gene (mutation).

Carrier Testing

This is a method of genetic testing that calculates the risk of being a carrier for the disorder. Carrier testing is only possible for females with a family history of DMD/BMD.

Since 2/3 of the mutations are intragenic deletions and the remaining 1/3 are single base pair changes anywhere within the gene, molecular analysis is not practical. In DMD and BMD there is a very wide diversity of mutations, so linkage analysis using polymorphic markers is a strong approach for carrier and/or prenatal diagnosis. 

How can we be sure that the diagnosis is 100% true and it is not mistaken? 

The diagnosis is very clear, using genetic and protein tests.
There are only two conditions, which may result in confusion in diagnosis to a doctor experienced in Duchenne dystrophy, and both of such conditions are other forms of muscular dystrophy (not DMD or BMD). Hence, diagnosis of DMD/BMD is pretty clear.

The somewhat similar types to DMD are autosomal recessive types, which are about 20 times rarer than the Duchenne type in boys. However, despite all the similarities, the specialised tests can distinguish between the two and identify the differences.

The Becker type of muscular dystrophy (BMD) is also somewhat similar to DMD. It is a milder type of dystrophin deficiency which may have some overlap in severity with the Duchenne type. It may be complicated in very young children to measure severity at first, but in the vast majority of cases the position is clear. Therefore, genetic and protein tests are used in order to make the difference clearer.

How can we be sure that no other boy in the family has it?

In order to find out if he is affected or not, creatine kinase blood test needs to be done. If he (at any age) has a normal creatine kinase level of blood, he is not affected and will never develop the disorder.

Can any carriers in the family be identified?

Although it may be more difficult, from the family tree it can be identified which women are at a risk of being carriers. This is done by geneticists who use creatine kinase and DNA blood test results to identify if such women are either carriers or reassure them that their risk is very low.

It is now available to all families to get genetic counselling or seek for specialised genetic advice at various clinical centres and hospitals.

Is it possible to diagnose DMD before birth (Prenatal diagnosis)?

Prenatal diagnosis in future pregnancies is often possible only once a child with DMD has been born in a family. Prenatal diagnosis can be offered either for the mother or for other women who are found to be at risk of being carriers.
This is normally done by examining the DNA of foetus in a chorion villus biopsy. This test is carried out at about the 11th-12th week of pregnancy, and is performed on a small piece of the developing placenta.

further information on such tests is available in the Muscular Dystrophy Campaign factsheet Carrier detection tests and pre-natal diagnosis.

How common is it?

The risk of having a DMD affected child, for the general population, is about 1 in every 3,500 male births. In the UK, about 100 boys with DMD are born each year. There are about 1,500 known boys with the disorder living in the UK at any one time.

BMD have a lower prevalence of 1 in 18,500 live male births.

Population genetics

In a 12-year study conducted in southern Italy, Nigro et al. (1983) found an incidence of DMD of 21.7 per 100,000 male live births and of BMD of 3.2 per 100,000. Of the DMD patients, 38.5% were familial; of the BMD cases, 50%.

Onengut et al. (2000) compared patterns of DMD gene deletions in 4 populations: Turks, Europeans, North Indians, and Indians from all over India. Statistical tests showed differences in the proportions of small deletions. In contrast, the distribution of deletion breakpoints and the frequencies of specific deletions commonly observed in the 4 populations were not significantly different. The variations strongly suggested that sequence differences exist in the introns, and that the differences are due to normal genetic distances among populations. The similarities suggested that some intronic sequences have been conserved and that those will trigger recurrent deletions.