Usher syndrome is a condition characterized by the gradual loss of both hearing and visual acuity in affected individuals. Hearing loss is progressive, bilateral, sensorineural and in the case of USH3A, post-lingual. Vision loss is caused by retinitis pigmentosa, a gradual deterioration of the retina, resulting in loss of night vision and subsequently peripheral vision. In about half of USH3A cases, patients also suffer from vestibular dysfunction, resulting in difficulties maintaining balance.
USH3A is a rare subset of Usher syndrome, representing about 2% of all Usher cases. However, due to founder mutations, it is found to be highly prevalent in the Finnish and Ashkenazi Jewish populations. Unlike other forms of Usher syndrome, type III has a later onset; hearing and vision problems usually develop during late childhood or adolescence. As a progressive disorder, the prognosis of USH3A remains bleak; by middle age, most affected individuals suffer from blindness and profound hearing loss.
An Usher syndrome diagnosis is dependent on the presence of bilateral sensorineural hearing loss and retinitis pigmentosa (RP). RP is confirmed based on fundoscopy findings of pigment deposits and a flat or diminished electroretinogram. While there is currently no cure for the condition, several treatments are available to improve symptoms. These include hearing aids, cochlear implants and low vision aids. Also, varied potential treatments are currently under research, including gene therapy, stem cell therapy and retinal implants.
The syndrome follows an autosomal recessive pattern of inheritance and is caused by homozygous or compound heterozygous mutations in the CLRN1 gene. This gene encodes clarin 1, a protein believed to play a role in actin filament organization, auditory receptor cell stereocilium organization, equilibrioception, photoreceptor cell maintenance and cell motility. Only 30 supposedly pathogenic variants of the CLRN1 gene have been annotated in the Human Gene Mutation Database. These include missense mutations, insertions or deletions.
Khan et al. (2017) studied a consanguineous Saudi family with four siblings affected by Usher syndrome. After an NGS panel of Usher genes and WES failed to identify mutations, a genome-wide linkage analysis and Whole Genome Sequencing (WGS) method were employed. This helped identify a homozygous deep intronic mutation, c.254–649T>G in the CLRN1 gene associated with USH3A. The mutation was predicted to generate a novel donor splice site and a CLRN1 minigene splice assay was carried out to study its effects. The mutation was shown to result in the splicing of an aberrant exon, resulting in a frameshift and a premature termination codon. This is the first reported case of a CLRN1 associated Usher diagnosis in Saudi Arabia. The authors also screened an additional 7 Saudi Usher patients and found the CLRN1 mutation in two of them. Microsatellite marker analysis indicated c.254–649T>G to represent a founder allele in the Saudi population. The authors stressed the benefit of using WGS to identify intronic hidden mutations in patients that do not carry exonic mutations.
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