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Usher syndrome

This is a heterogeneous group of diseases. The association of sensorineural deafness and progressive retinitis pigmentosa is the hallmark of Usher syndrome.

Usher syndrome is subdivided into 3 different types:

Type 1:

Usher syndrome type I is characterized by congenital, bilateral, profound sensorineural hearing loss. Patients do not develop speech. Retinitis pigmentosa (RP) is typical, with progressive, bilateral, symmetrical degeneration of the cells that are responsible for night vision (rod) and regular day vision (cone cells). This usually develops in adolescence, resulting in night blindness, progressively constricted visual fields, and impaired visual acuity. All patients have vestibular dysfunction.

Genes involved: At least 7 different genes have been found to cause this phenotype. The most common is MYO7A, which produces the protein Myosin7a. This gene is located on chromosome 11q13.5. Other genes are USH1C, which produces the protein Harmonin and is situated on chromosome 11q15.1; CDH23, which produces the protein Cadherin 23 and is located on chromosome 10q22.1; PCDH15, which produces the protein Protocadherin 15 and is located on chromosome 10q22.1; SANS, which produces the protein SANS and is situated on chromosome 17q25.1; and other genes on chromosomes 14q32 and 21q21.

Recently a unique mutation in the PCDH15 gene, R245X, has been identified. This is specific to and common among Ashkenazi Jews with Usher syndrome type 1. The carrier frequency in the healthy Ashkenazi Jewish population is between 1:40 and 1:100. No R245X carriers have been detected among other Jewish or non-Jewish population controls, indicating that this mutation may be unique to Ashkenazi Jews.

Type 2:

Usher syndrome type II is a milder condition, characterized by congenital, bilateral, sensorineural hearing loss that is limited to the higher frequencies and that ranges from mild to severe. Mild progression of hearing loss occurs with age. Speech development benefits from hearing aids and speech therapy. Vestibular impairment is variable. Retinitis pigmentosa (RP), a progressive, bilateral, symmetrical degeneration of rod and cone functions of the retina, develops in adolescence or early adulthood and results in progressively constricted visual fields and impaired visual acuity. Genes involved: At least 3 different genes have been found to cause this phenotype. The most common is USH2A, which produces the protein Usherin and is located on chromosome 1q41. There are other genes on chromosomes 3p23 and 5q14-21.3.

Type 3:

This third classification, USH3, is found most frequently among Finnish patients, where the hearing loss and retinitis pigmentosa are progressive, with variable vestibular dysfunction.

Genes involved: At least 2 different genes have been found to cause this phenotype. The most common is USH3A, which produces the protein Clarin 1 and is located on chromosome 3q25.1, and there is also another gene on chromosome 20q. Several families of Ashkenazi and Yemenite Jews have been found to carry a mutation in the USH3A gene, but overall the carrier frequency for this type is very low.

Inheritance pattern of these types of Usher syndrome

Autosomal recessive.


Full, there is variability at age of onset, correlating to the severity.

Associated features that can be demonstrated in tests performed during pregnancy

There are no specific ultrasound signs or associated defects.

What is the risk of recurrence in a subsequent pregnancy?

For a couple who has already had an affected child, the risk is 25% in every subsequent pregnancy. This also applies to a couple where both partners have been found to carry mutations for Usher syndrome.

When only one parent carries the abnormal gene, there is no risk that any of their offspring will have the disease; however, in such families there is a 50% chance that the infant will be a carrier, but he himself will be healthy, like the carrier parent.

The risk for more distant relatives depends on the degree of relationship between the relatives and the affected individuals, the ethnic groups of their partners, the presence of family members with Usher syndrome in the partners' families, consanguinity between the parents, if present, etc. The risk is established within genetic counseling.

Molecular genetic information

Gene, Location: see above for each specific type

Genetic testing

Diagnostic testing

For most families it is not easy to identify the genetic defect since there are many different genes involved in each clinical type. Usually the mutation in different families is different, and therefore genetic tests are offered today on a research basis - families with many affected individuals are more informative for such a task. In informative families the gene involved can first be identified by linkage study - this requires testing DNA samples from as many members of the family as possible. See: Indirect testing for genetic markers in a family that has one or several patients - when there are a number of genes that can each cause the disease - the gene, or most of the genes not having been located / identified / mapped - autosomal recessive diseases

Only in a few types of Usher syndrome, where a common and typical mutation exists, a direct test can be performed to identify the mutation in the gene. An example is the mutation R245X in the PCDH15 gene among Ashkenazi Jews with type 1 Usher syndrome. This is done by testing for the specific mutations that are common in the specific Usher syndrome type and according to the patient's ethnic origin. See: Testing the disease-causing gene for mutations that are common in specific ethnic group - autosomal recessive diseases.

Carrier testing

Patient and Carrier testing among Ashkenazi Jews Among Jews, most of the affected children have been type 1 and have been found to be of Ashkenazi origin. As described, the mutation that is specific to and common among this group is R245X in the PCDH15 gene, and the carrier rate is between 1:40 and 1:100.

In view of this, it is very important to ascertain the ethnic origins of the couple, and it is advisable to examine (carrier DNA testing) those couples where both partners are fully or even partially of Ashkenazi Jewish origin. Of all the types of Usher syndrome in Israel, the only one that is offered for screening among Ashkenazi Jews is that caused by the mutation R245X in the PCDH15 gene. Mutations in other genes involved in Usher syndrome, both in Jews and non-Jews, are very rare and do not justify general screening.

It is important that relatives of patients with Usher syndrome clarify which mutations are present in the patient or parents in their family in order to ascertain that they are included in the battery of mutations routinely tested for - otherwise it will be necessary to expand the list of mutations tested for and/or examine the partner. This will be discussed in genetic counseling.

See also: "Introduction to population DNA screening for autosomal recessive diseases such as Cystic fibrosis and others".

Fetal testing

Same as the diagnostic test. See above for each specific type

Prenatal diagnosis (amniocentesis) can also be offered to each couple who has had an affected child. The best way is after identifying the mutations in the parents, but if these are not found, indirect linkage analysis can be performed. See: Indirect testing for genetic markers in a family that has one or more patients - when there is only one gene that can cause the disease - autosomal recessive diseases.

Preimplantation diagnosis (before the embryonic cells implant in the uterine wall) can also be offered only if the mutation causing the disease has been identified in the parents. In such limited number of families, this is performed in special centers, and in special cases this can be considered within genetic counseling.
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