Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Usher Syndrome

Dr. rer. biol. hum. S. Chahrokh-Zadeh

Scientific Background

Usher syndrome (USH) is a group of clinically and genetically heterogeneous, autosomal recessive diseases with bilateral, sensorineural hearing loss, vestibular dysfunction and gradual retinal degeneration, retinitis pigmentosa (RP). It is the main cause (> 50%) of deaf-blindness. Prevalence is estimated to be 1:6,000. The three main subtypes USH1, USH2 and USH3 are mainly distinguished by the severity and progression of deafness and the presence of vestibular defects. Several genes and one so-called modifier gene (PDZD7) have been identified so far.

The most commonly occuring subtype involves USH2 (moderate to severe hearing loss, RP usually after puberty, and normal vestibular function). Most of the pathogenic variants can be detected in the USH2A gene (USH2A; 57%-79%).

USH1 represents 30-40% of all USH types and is the most severe form with high-grade congenital deafness, onset of visual impairment (RP) before puberty and frequently, vestibular dysfunction. Patients with USH1 are often not diagnosed with hearing loss until the reduced field of vision (tunnel vision) and night blindness (first signs of RP) have progressed so far that they become evident. However, an early diagnosis is important for adequate schooling and support in childhood. Classification of the single subtypes based on clinical data is unsatisfactory as there is high phenotypic variability, and it can be very high even if there are identical variants. So far 9 loci and 6 genes are known: 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 above mentioned genes are also described in patients with autosomal recessive, non-syndromic, congenital or prelingual deafness, e.g. MYO7A in DFNA11 (autosomal dominant) and DFNB2 (autosomal recessive), CDH23 in DFNB12 and PCDH15 in DFNB23. Digenic inheritance, with a mutation in one of each affected genes is also known, e.g. CDH23 and PCDH15 or PDZD7 and ADGRV1. Autosomal recessive, non-syndromic, congenital or prelingual deafness is genetically heterogeneous, with more than 70 genes known to date and approximately 23 loci, whose genes are currently unknown.

Literature

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