DNA DIAGNOSTICS

    At this moment, 10 different Usher Syndrome genes are known, each of which is involved in the production of an Usher protein. The various genes are divided into three clinical images and indicated by a letter.

    The division into the three clinical images is as follows:

    1children suffering from Usher Syndrome type 1 are born deaf and their organ of balance does not work. The first signs of night-blindness and an ever narrowing field of vision appear during childhood.

    2children suffering from Usher Syndrome type 2 are born hard of hearing and the first signs of deteriorating eyesight appear around puberty.

    3children suffering from Usher Syndrome type 3 are born with good hearing or hard of hearing, but their hearing and eyesight deteriorate during childhood.

    Also, Usher genes are known mutations in which may lead to non-syndromic loss of hearing. In this case, no retinitis pigmentosa (RP) will be developed. These mutations are particularly found in Usher 1 genes and in the USH2D gene. Besides, the USH2A gene also knows mutations that cause non-syndromic retinitis pigmentosa. These patients do not or hardly loose their hearing.

    MANY VARIETIES

    There is still a lot of variation in the seriousness of the disease. This depends on the nature of the individual mutations and the specific combination of the USH mutations. Consequently, it is very well possible to suffer from Usher Syndrome type I but to have a loss of hearing and/or a stage of RP that is similar to someone suffering from type 2. Or to resemble a patient with Usher Syndrome type 3 while having been diagnosed for Usher Syndrome type 1.

    2 MUTATIONS IN 1 GENE

    People are diagnosed for Usher Syndrome, because they have two mutations in an Usher gene (the hereditary material). One mutation coming from the father and one from the mother. Usher Syndrome will not be developed when, for example, a mutation in the USH1 gene from the father and a mutation in the USH2 gene from your mother. Usher Syndrome will not be developed if, for example, a mutation in the USH1 gene is inherited from the father and a mutation in the USH2 gene from the mother. The two mutations found in one of the Usher genes passed on from father and mother can be different (heterozygous) or identical (homozygous).

    THE GENETIC OUTCOME

    The genetic outcome is usually communicated by an ophthalmologist, an ENT specialist or a clinical geneticist. But how to read this outcome? What goes wrong in the DNA and what does this mean?

    10 USHER GENES

    By now, 10 genes are known to be responsible for a certain type of Usher Syndrome. For each Usher gene a lot of different mutations are known. Mutations are changes in the hereditary material.
    Over 500 different mutations have been found in only the USH2A gene, all of which result in an improper (or insufficient) production of the Usherin protein.

    If there are no mutations (or 1 mutation) in the Usher gene, the Usher protein is produced and the ears and eyes will function properly.
    The Leiden Open Variation Database contains over 20K varieties of mutations in the 10 different USH genes. New screening technologies still lead to new gene-related discoveries and these are added to the database in Leiden, the Netherlands.

    DNA RESEARCH

    It is to be determined by means of an extensive examination whether (serious) loss of hearing and retinitis pigmentosa (retina degeneration – RP) are involved. In order to make the correct diagnosis, a DNA test is required. After all, more syndromes are known (although very rare) that also affect these two senses.

    For a DNA test a small vial of blood is taken and a special laboratory will examine this for changes that can explain the loss of hearing and eyesight. Sometimes a vial of blood from one of the parents is required as well to see if the changes are coming from one parent or have been inherited from both parents.

    RESEARCH INTO HEREDITY

    ‘Next Generation Sequencing Technology’ is research focused on the molecular diagnosis of Usher Syndrome into not yet localised Usher mutations in both exons and introns with types 1, 2 and 3. Exons and introns are small parts of a gene that eventually contains the information for producing the correct protein.

    The enormous variety in Usher genes, the sizes of these genes and the different mutations make unravelling Usher Syndrome really complex. Research into Usher Syndrome includes many challenges.

    FROM DNA TO PROTEIN

    The hereditary material of each person is stored in the DNA. The DNA consists of many genes. Each gene contains the code for the production of a protein. Proteins are the building blocks of our bodies. Reading this code for producing a protein is a complicated process.

    NETWORKING

    Researchers extensively studied how the various USH proteins bond together to form functional networks in the hair cells and photoreceptors.
    They think they completely know these networks for USH 1, USH 2 and USH 3 and with that all associated proteins as well.

    These networks contain only one protein which at this moment is not an USH protein. This is PDZD7, which forms a part of the networks of USH2 proteins. Mutations in this protein seem to cause only deafness. Whirlin is suspected to be able to compensate the functioning of PDZD7 in the eye but not in the ear. The fact is that these two proteins are very much alike.

    Based on the similarity of the development of the disease it is thought that possibly four other genes may be associated with USH: PDZD7, HARS/USH3B, CEP250 and C2orf71. The interpretation may sometimes vary in different laboratories, e.g. some literature accepts USH 3B as USH gene and some literature only speaks of a possible association.

    For USH 1E, 1H and 1K genomic regions have been defined, but genes with causal mutations have never been found in these regions. Expectations are that additional genetic analysis will show that these people still have mutations in one of the already known USH 1 genes.

    In the Netherlands, people preferably take the work of Dr José Millán from Valencia, Spain, as a basis. He is the authority in the area of USH genetics in Europe. For a complete list of the presently known USH genes and mutations, please look here. This list comes from the publicly accessible on-line platform OMIM (Mendelian Inheritance in Man).

    The Usher protein network. Red: associated with Usher Syndrome, Blue: associated with isolated RP and Black: associated with isolated deafness. Credits Erwin van Wijk

    EXOME SEQUENCING

    Exome Sequencing is a technique with which all 20.000 genes of one person can be recorded in one go. This technique is also called Whole Exome Sequencing (WES). Simultaneously studying several genes increases the chance of finding the cause of Usher Syndrome.

    First of all, the changes in genes that are known to cause Usher Syndrome are studied. If no deviations are found, the other genes will be studied, provided that permission is given for this.

    • WES examination: A WES examination (‘Whole Exome Sequencing’) may include all 20,000 genes. When a child is to have a WES examination, the DNA of the parents is usually examined as well (‘Trio-WES’). This in order to be able to compare the genes of the parents with those of the child.
    • WGS (Whole Genome Sequencing) studies not only the genes, but the DNA between the genes as well. Presently, this is usually done in scientific research.