Usher syndrome is a genetic disorder that affects both hearing and vision. It is characterized by sensorineural hearing loss and retinitis pigmentosa (a progressive vision disorder). Individuals with Usher syndrome may also experience balance issues due to vestibular dysfunction. It is a leading cause of deaf-blindness. The prevalence of the syndrome is estimated at approximately 3-6.2 cases per 100.000 population.
Usher syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Key features and aspects of Usher syndrome include:
- Genetic Basis: Usher syndrome is primarily caused by gene mutations associated with the inner ear and retina's development and function. There are three main types of Usher syndrome: Type 1, Type 2, and Type 3. Each type is associated with mutations in different genes.
- Hearing Loss: Sensorineural hearing loss is a common feature of Usher syndrome. The degree of hearing loss varies among individuals and can range from mild to profound. Type 1 typically involves congenital deafness, while Type 2 is associated with moderate to severe hearing loss from birth.
- Retinitis Pigmentosa: Retinitis pigmentosa is a degenerative eye disorder that affects the retina, leading to progressive vision loss. Night blindness and tunnel vision are early symptoms, followed by a gradual loss of peripheral vision. Central vision may also be affected later in the disease course.
- Vestibular Dysfunction: Individuals with Usher syndrome may experience vestibular dysfunction, which can lead to difficulties with balance and coordination. This can result in problems with walking and a higher risk of falls.
- Onset and Progression: The onset and progression of symptoms can vary among individuals, as well as the different types of Usher syndrome. Type 1 tends to have an earlier onset and more rapid progression of symptoms compared to Type 2 and Type 3.
- Genetic Testing and Diagnosis: Diagnosis of Usher syndrome involves a combination of clinical evaluation, audiometric testing, and genetic testing to identify mutations in the associated genes. Genetic counseling is often recommended for affected individuals and their families.
- Management and Treatment: There is currently no cure for Usher syndrome, and treatment focuses on managing symptoms and providing support. Hearing aids, cochlear implants, and communication strategies can help individuals with hearing loss. Orientation and mobility training, adaptive devices, and assistive technologies may assist those with vision loss. Ongoing medical monitoring and psychological support are also necessary.
- Research: Research is ongoing to explore potential treatments for Usher syndrome, including gene therapies and other interventions to slow the progression of vision and hearing loss.
Usher syndrome is a complex and challenging condition that requires a multidisciplinary approach involving audiologists, ophthalmologists, genetic counselors, and other healthcare professionals. Early diagnosis and intervention can help individuals and their families better manage the syndrome's impact on their lives.
More Information
10 different genes have been described that are associated with the three clinical types of Usher syndrome. The MYO7A, USH1C, CDH23, PCDH15, USH1G, and CIB2 genes are related to Usher syndrome type 1; the USH2A, ADGRV1, and WHRN genes are responsible for Usher syndrome type 2; and CLRN1 is the only gene associated with Usher syndrome type 3. However, this relationship is not strict; for example, there are cases of patients with variants in MYO7A and CDH23 diagnosed with Usher syndrome type 2 when both genes are associated with Usher syndrome type 3.
In this test, we include an analysis of specific pathogenic variants found in the MYO7A, USH1C, CDH23, PCDH15, USH2A, ADGRV1, and CLRN1 genes.
In general, the mode of inheritance of Usher syndrome is autosomal recessive. In patients, the pathogenic variants can occur in homozygosis (two copies of the same mutation) and in compound heterozygosis (two copies resulting from the combination of two different mutations). However, in the case of the MYO7A gene, it has been shown that there are variants for which it can follow an autosomal dominant mode of inheritance. Cases of digenic inheritance (two pathogenic variants, one in a gene related to the syndrome and another pathogenic variant in a second associated gene) have also been observed, for example, a variant in CDH23 and another variant in PCDH15 or a variant in GPR98 and another variant in PDZD7.
The MYO7A gene is usually mutated in Usher syndrome type 1 patients (MYO7A variants account for 50% of cases). The gene produces a myosin VIIA protein, a motor protein involved in intracellular trafficking. This type of myosin, included in the “unconventional myosins” group, is expressed in the retina's photoreceptor cells, the retinal pigment epithelium, and inner ear cells.
The USH1C gene encodes for the harmonin protein that organizes protein complexes and binds to the USH1 and USH2 proteins, although its expression is ubiquitous, it is especially high in mechanosensitive hair cells of the inner ear and photoreceptor cells of the retina. The c.216G>A (p.Val72=) variant of USH1C is common in patients of French-Acadian ancestry with USH1.
CDH23 is the second most frequently mutated gene in USH1 patients. This gene produces a structurally functional protein called cadherin-23 that is necessary to develop and organize stereocilia in the cell and coat properly.
The PCDH15 gene encodes for protocadherin-15, which is involved in cell adhesion. The c.733C>T (p.Arg245Ter) variant in the PCDH15 gene introduces an early stop coding that leads to the generation of a truncated, nonfunctional protein. It is especially prevalent in the Ashkenazi Jewish population, with a typical frequency of 0.4%, while in the general population, it is 0.019%.
The USH2A gene encodes for usherin, expressed in the basement membrane of the cell and retina, which is essential for proper development and maintenance. Mutations c.2299delG (p.Glu797fs) and c.2276G>T (p.Cys759Phe) have been linked to USH2. The c.2299delG causes an alteration of the readout pattern, generating a premature stop codon and a non-functional truncated protein. The c.2276G>T causes a non-conservative amino acidic change, impacting the secondary structure of usherin and its functionality.
The ADGRV1 gene produces the calcium-binding G-protein-coupled receptor, which is abundant in the central nervous system. It plays an essential role in the development of hearing and vision. Mutations in this gene result in USH2.
The CLRN1 gene encodes for clarin-1, which is involved in the sensory synapses of balance, sound, and vision perception. The c.144T>G (p.Asn48Lys) mutation is associated with USH3. It has been observed in patients in homozygosity and combination with another mutation related to the syndrome. It is especially prevalent in the Ashkenazi Jewish population (with a frequency of 0.5%), probably due to a founder effect. Another founder mutation in CLRN1, c.528T>G (p.Tyr176Ter), is present in Finland and found in patients from the USA and Sweden.
In total, Usher syndrome genetic testing analyzes the 3 most frequent pathogenic mutations of ADGRV1 gene plus the 4 most frequent pathogenic mutations of CDH23 gene plus the 5 most frequent pathogenic mutations of CLRN1 gene plus the 28 most frequent pathogenic mutations of MYO7A gene plus the 5 most frequent pathogenic mutations of PCDH1 gene plus the 2 most frequent pathogenic mutations of USH1C gene plus the 48 most frequent pathogenic mutations of USH2A gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
