Description

Scientific Background

Usher Syndrome (USH) a group of clinically and genetically heterogeneous autosomal recessive diseases with bilateral sensorineural hearing loss, including vestibular dysfunction, gradual retinal degeneration, and retinitis pigmentosa (RP), is the major cause (>50%) of deaf-blindness. The prevalence is estimated at 1:6000. Three main subtypes, USH1, USH2 and USH3, are distinguished mainly by the severity and progression of the hearing loss and the presence of vestibular defects. So far, several genes and a modifier gene (PDZD7) have been identified.

The most common subtype is USH2 (moderate to severe hearing loss, PR usually after puberty, and normal vestibular function). Most pathogenic variants are detectable in the USH2A gene (USH2A; 57%-79%).

USH1 accounts for 30-40% of all USH types and is the most severe form with severe congenital deafness, onset of visual impairment (RP) before puberty and often vestibular dysfunction. Patients with USH1 are often diagnosed with hearing loss alone until the reduced field of vision (tunnel vision) and night blindness (first signs of RP) have progressed so far that they are noticeable. However, an early diagnosis is important for adequate schooling and support in childhood. The classification of individual subtypes based on clinical data is unsatisfactory as the phenotypic variability can be very high, even in the presence of identical variants. Nine loci and 6 genes are known at this time: MYO7A (USH1B; 53%-63% of all USH1), USH1C (USH1C; 1%-15%), CDH23 (USH1D; 7%-20%), PCDH15 (USH1F; 7%-12%), USH1G (USH1G) and CIB2 (USH1J). Other genes are also discussed in this context.

Pathogenic variants in the genes listed above are also described in patients with autosomal recessive, non-syndromic, congenital or prelingual hearing loss, e.g., MYO7A in DFNA11 and DFNB2, CDH23 in DFNB12, and PCDH15 in DFNB23. Digenic inheritance, each with one variant in one of the affected genes, e.g., CDH23 and PCDH15, or PDZD7 and ADGRV1, is also known. Autosomal recessive, non-syndromic congenital or prelingual hearing loss is genetically heterogeneous, with more than 70 known genes to date and approximately 23 loci whose genes are still unknown.

References

Jouret et al. 2019, Otol Neurotol 40:121 / Krawitz et al. 2014, Mol Genet & Genomic Med 2:393 / Rong et al. 2014, PLOS ONE 9:e97808 / García-García et al. 2013, Mol Vis 19:367 / Kimberling et al. 2010, Genet Med. 12:512 / Ebermann et al. 2010, J Clin Invest 120:1812