Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause of combined deafness and blindness. It has a worldwide prevalence of 3.2/100,000 – 6.2/100,000 1. Clinically, USH is divided into three types as indicated in Table 1.
- Usher type I (USH1) - the most severe form
- Usher type II (USH2) - moderate to severe form
- Usher type III (USH3) – mild to moderate form
Table 1: Overview of Usher syndrome subtypes
|Usher syndrome||Type 1||Type 2||Type 3|
|Genes||MY07A, USH1C, CDH23, PCDH15, USH1G, CIB2||USH2A, ADGRV1, WHRN||CLRN1|
|Hearing||Profound deafness in both ears from birth||Moderate to severe hearing loss from birth||Normal at birth; progressive loss in childhood or early teens|
|Vision||Decreased night vision before age 10||Decreased night vision presenting in late childhood/adolescence||Varies in severity; night vision problems often begin in teens|
|Vestibular function||Balance problems from birth||Normal||Normal to near-normal, chance of later problem|
Usher syndrome type I (USH1) is the most severe form, characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive retinitis pigmentosa (RP). USH1 patients are either born completely deaf or experience hearing impairment within the first year of life and usually do not develop speech. Constant vestibular dysfunction is present from birth; children have delays in motor development and begin sitting independently and walking later than usual. Onset of retinitis pigmentosa occurs during childhood, resulting in a progressively constricted visual field and impaired visual acuity which rapidly proceeds to blindness. Anomalies of light-evoked electrical response of the retina can be detected by electroretinography at 2-3 years of age, which allows for early diagnosis of the disease.
Usher syndrome type I should be suspected in individuals with:
- Congenital (i.e., prelingual) profound bilateral sensorineural hearing loss
- No significant vestibular responses
- Retinitis pigmentosa (RP)
- Normal general health and intellect; otherwise normal physical examination
- A family history consistent with autosomal recessive inheritance.
Six genes associated with Usher syndrome type I so far are: MYO7A, USH1C, CDH23, PCDH15, USH1G, and CIB2 (Table 2).
Usher syndrome type II (USH2) is the most common of the 3 Usher syndromes. Patients with USH2 patients have mild hearing impairment with normal vestibular responses, and retinitis pigmentosa. Hearing loss is congenital but may be detected at later stages when it hinders communication. The degree of hearing impairment in patients diagnosed with USH2 increases from moderate in low frequencies to severe in high frequencies, tending to remain stable.
Usher syndrome type II (USH2) should be suspected in individuals with:
- Congenital sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies
- Intact vestibular responses
- Retinitis pigmentosa
- Normal general health and intellect; otherwise normal physical examination
- A family history compatible with autosomal recessive inheritance.
Usher syndrome type II is associated with the genes USH2A (accounts for ~80% of all cases), ADGRV (6.6%-19%) and WHRN (<9.5%)10.
Usher syndrome type III is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life. Usher syndrome type IIIA (USH3A) is caused by homozygous or compound heterozygous mutations in the CLRN1 gene. Usher syndrome type III is the least common clinical type of the syndrome in the general population. However, in some populations, like such as the Finns or the Ashkenazi Jews, thise syndrome accounts for over 40% of USH cases due to the mutation founder effect of c.300T>C (p.Y176X; known as the Finn mayor mutation) and c.143T>C (p.N48K), respectively 1.
Table 2: The overview of genes associated with Usher syndrome
|Locus||Protein||Allelic/associated disorders (OMIM)|
|5q14.3||6.6%-19% for USH26, 7||USH2C (605472); Febrile seizures 4 (604352)|
|10q22.1||7%-20% of USH11||Deafness, autosomal recessive 12 (601386), Usher syndrome type 1D/F (601067)|
|15q25.1||Few individuals||USH1J (614869); DFNB48 (609439)|
|3q25.1||Few individuals||USH3A (276902); RP61 (614180)|
|DFNB31 (WHRN) |
|9q32||0%-9.5% of USH26, 7||DFNB31 (607084); USH2D|
|11q13.5||53%-63% of USH11 |
8% (4/53) of DFNA/DFNB3
|DFNA11 (601317); DFNB2 (600060), USH1 (276900)|
|10q21.1||7%-12% for USH18, 9||USH1D (601067); DFNB23 (609533); USH1F (602083)|
|10q24.31||Few individuals||USH2C (605472); USH2A (276901)|
|11p15.1||1%-15% of UCH11, 4 |
1.65%-12.5% of USH15
|DFNB18A (602092); USH1C (276904)|
|17q25.1||0%-4% for USH11||USH1G (606943)|
|1q41||57%-79% for USH2 6, 7||USH2A (276901); RP39 (613809)|
Abbreviations: DFNA-Deafness non-syndromic autosomal dominant; DFNB-Deafness non-syndromic autosomal recessive; USH-Usher syndrome.
The ADGRV1 gene, associated with Usher syndrome type 2C, encodes a large transmembrane protein involved in adhesion and migration processes. Alterations in the ADGRV1 gene account for approximately 6.6%-19% of all Usher syndrome type 2 cases6, 7. More than 100 variants have been reported in the ADGRV1 gene so far, mostly missense mutations (65%) and small deletions (25%)1, 6, 7.
The CDH23 gene, associated with USH1D, encodes protein cadherin 23. Cadherin 23 is a glycosylated transmembrane protein responsible for cell adhesion, migration, and differentiation. Pathogenic variants in CDH23 are responsible for ~7%-20% of all Usher syndrome affected cases 1. At least 150 pathogenic variants have been reported in CDH23. Most of the variants associated with Usher syndrome type ID are null (nonsense, frameshift, splice site) and result in a more severe phenotype than missense variants1. Furthermore, a large deletion resulting in the loss of three exons was also reported in a Japanese patient.
The CIB2 gene, associated with USH1J, encodes calcium- and integrin-binding protein that mediates intracellular calcium signaling. Five missense mutations have been reported so far, including a single base pair pathogenic variant (c.192G>C) identified in 52 out of 54 Pakistani families affected with Usher syndrome1.
The DFNB31 gene, also known as WHRN, is associated with Usher syndrome type 2D. This gene encodes protein whirlin, scaffold protein similar s to harmonin (USH1C). Alterations in DFNB31 are linked to <9.5% of Usher syndrome type 2 affected cases6, 7. Several missense mutations in this gene are also associated with nonsyndromic autosomal recessive hearing loss1.
The MYO7A gene causing which causes Usher syndrome type 1B, encodes a myosin VIIa protein that belongs to a group of myosins. Myosins are ATP-driven motor molecules that move along actin filaments and may be involved with intracellular transport mechanisms. More than 300 pathogenic variants have been reported in the MYO7A gene and thesey are located throughout the gene, although many are clustered in the exons that encode conserved domains of the protein. A relatively high percentage of identified mutations (37%) identified so far are missense variants2. Approximately 53%-63% of patients affected with USH1 are carrying disease-causing variants in the MYO7A gene1, 3. Pathogenic MYO7A variants also cause autosomal dominant nonsyndromic hearing loss (DFNA11). MYO7A variants associated with autosomal recessive nonsyndromic hearing loss (DFNB2) have also been reported.
The PCDH15 gene, associated with USH1F, encodes protocadherin 15, a member of cadherine family that regulates cell adhesion, migration and differentiation. Pathogenic variants in this gene are responsible for 7%-12% of Usher syndrome cases1, 8, 9. At least 50 different pathogenic variants have been reported1. Many of the single nucleotide variants are private and null, and there are no mutational hotspots. Deletions/duplications account for 37% of PCDH15 pathogenic variants. The Ashkenazi Jewish founder variant c.733C>T has a carrier frequency in the Jewish population (0.79%-2.48%)9.
Usher syndrome type IIC (USH2C) is caused by homozygous or compound heterozygous mutations in the ADGRV1 gene and it is also caused by biallelic digenic mutations in the ADGRV1 and PDZD7 genes1.
The USH1C gene, associated with USH1C, encodes protein harmonin that which is required for normal cochlear cells development. More than 20 pathogenic variants have now been reported in this gene, with a mutation frequency of 1%-15%1, 4, 5. The first USH1C pathogenic variants identified include the Acadian founder variant c.216G>A, which was shown to create a cryptic splice donor in exon 3 affecting mRNA stability and usage of the normal exon 3 splice donor4. One allele of a polymorphic 45-nucleotide variable number of tandem repeats c.496+59_496+103 present in intron 5 was found to be in complete linkage disequilibrium with the Acadian USH1C founder variant c.216G>A. Outside the Acadian population of Louisiana, the total contribution of USH1C pathogenic variants to the Usher syndrome type I phenotype ranges from 1.65% to 12.5%5. The most common USH1C pathogenic variant observed in persons from other ethnic origins is c.238dupC1. Mutations in the USH1C gene are also associated with infantile hyperinsulinism, enteropathy, and deafness and with autosomal recessive nonsyndromic hearing loss (DFNB18).
The USH1G gene, associated with USH1G, encodes a SANS protein that plays a role in regulating endocytosis-dependent ciliogenesis. At least ten pathogenic variants have been reported, including a 20-nucleotide homozygous deletion (p.Ser278ProfsTer71) found in the original consanguineous Palestinian family1. A second homozygous variant (p.Val132GlyfsTer3), found in a large consanguineous Tunisian family, was important in refining the location of USH1G. Recently a homozygous pathogenic variant (p.Ser243Ter) was found in cochlear-implanted Saudi siblings with cochlear implants, with some atypical retinal findings1.
Currently, there is no treatment for Usher syndrome. The hearing loss can be addressed by the use of hearing aids and cochlear implantation, but the retinal problem remains unsolved. Many clinical trials are currently ongoing with the aim of discovering a new treatment for Usher syndrome.
CENTOGENE offers sequencing and deletion/duplication analysis of the genes in the Usher syndrome panel (ADGRV1, CDH23, CIB2, CLRN1, DFNB31, MYO7A, PCDH15, PDZD7, USH1C, USH1G, USH2A).
The differential diagnosis of Usher syndrome includes the following diseases - depending on the major presenting symptoms:
- Nonsyndromic hearing loss (NSHL) associated with mutations in GJB2 and GJB6
- Nonsyndromic retinitis pigmentosa, caused by mutations in RHO, PRPF31, RP1, ABCA4, CERKL, CRB1 or other RP-related genes
- Deafness-dystonia-optic neuronopathy (DDON), caused by mutations in TIMM8A
- Oculo-acoustic syndromes associated with mitochondrial DNA mutations (MIDD, Kearns-Sayre syndrome)
- Refsum disease caused by mutations in PHYH or PEX7
- Moderate forms of Alström syndrome caused by mutations in ALMS1
- Waardenburg syndrome (WS) caused by mutations in PAX3, EDNRB, EDN3, and SOX10
- Viral infections, diabetic neuropathy, and syndromes involving mitochondrial defects.
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Usher syndrome using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Usher syndrome panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no clinically relevant variant is identified after analysis of the Usher syndrome panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
The following individuals are candidates for Usher syndrome gene testing:
- Individuals with a family history of Usher syndrome and presentation of the most common symptoms, including visual and hearing abnormalities
- Individuals without a positive family history, but with symptoms resembling Usher syndrome
- Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).
Sequencing, deletion/duplication of genes related to Usher syndrome should be performed in all individuals suspected of having Usher syndrome. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of Usher syndrome, identify at-risk family members, provide information on reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.
More information on CENTOGENE´s Usher syndrome panel can be found in our genetic test catalogue.