Abstract
Abstract Usher syndrome (USH) manifests with congenital and apparently isolated hearing loss, followed by retinal degeneration in later life. Therefore, and because of its high prevalence in the congenitally hearing-impaired population, USH is one of the most relevant deafness syndromes. Next-generation sequencing (NGS)-based testing can now provide most analyzed USH patients with a molecular diagnosis, based on mutations in 11 genes. Given the availability of several excellent articles on the clinical and biochemical basis of USH, this short review focuses on critical assessment of new genes announced as USH genes, clinical and genetic differential diagnoses and therapeutic developments. Because obsolete loci, disproved USH genes and the inclusion of genes whose mutations cause similar phenotypes have increasingly blurred genetic classification, a revision based on phenotype restricted to genes related to the Usher protein complex is proposed.
Highlights
Usher syndrome (USH) manifests with congenital and apparently isolated hearing loss, followed by retinal degeneration in later life
In contrast to non-syndromic RP or deafness, with probably many more rare genes to be discovered that account for the ≥30 % of cases that remain mutation-negative after comprehensive Next-generation sequencing (NGS) panel analysis, the genes for USH have essentially been found
While genomic sequencing of the USH genes is manageable for specialized diagnostic institutions, analysis of the effect on splicing is beyond the scope of most labs and not covered by reimbursements provided by the health insurances
Summary
Usher syndrome (USH) is an autosomal recessive trait currently known to result from mutations in 11 genes. The USH gene loci have numeric and alphabetic designations according to the clinical subtype and the order of their initial descriptions USH2: This is the most common (two-thirds of the cases) and mildest clinical subtype. USH3: This subtype is very rare in Central Europe, but common in some founder populations (Finland, Québec, Louisiana). Hearing loss is congenital and progressive and may require CI supply. Clinical expression of mutations in the USH3 gene, CLRN1, is clinically quite variable and may present with a severe course indistinguishable from USH1. Atypical USH: Clinical manifestations differing from the above subtypes have been described in patients with pathogenic biallelic variants in USH genes. Atypical USH applies to courses with late onset of either hearing loss or RP, or to unusually severe or mild expression of USH2 and USH1 gene mutations, respectively.
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