Usher Syndrome, Type Iv

A number sign (#) is used with this entry because of evidence that Usher syndrome type IV (USH4) is caused by homozygous mutation in the ARSG gene (610008) on chromosome 17q24.

Description

An atypical form of Usher syndrome, here designated type IV, is an autosomal recessive disorder characterized by late onset of retinitis pigmentosa and usually late-onset of progressive sensorineural hearing loss without vestibular involvement (summary by Khateb et al., 2018).

For a discussion of genetic heterogeneity of Usher syndrome, see 276900.

Clinical Features

Khateb et al. (2018) described 5 patients from 3 Yemenite Jewish families (MOL0120, MOL0737, and TB55) with an atypical form of Usher syndrome. All affected individuals presented with a distinctive late-onset retinal phenotype, including ring-shaped retinal atrophy delimiting the vascular arcades temporally and extending beyond the optic nerve nasally, with relative preservation of the mid- and far-periphery. Over time, pigment migration occurred within the atrophic areas, forming bone-spicule-like pigmentary changes as well as pigment clumps, and the central macula also became involved. Electroretinographic testing showed severely decreased rod and mixed cone-rod responses. Electrooculography testing, which was performed on 3 patients, showed that the Arden ratio was reduced, suggesting injury to the retinal pigment epithelium, either as a primary event or secondary to photoreceptor degeneration. None of the patients reported significant abnormalities of the vestibular system. Affected sibs from 2 families presented with progressive moderate to severe sensorineural hearing loss at a relatively late age, usually after age 40; hearing loss in the single patient from the third family began in childhood and deteriorated around the age of 18.

Mapping

By homozygosity mapping followed by whole-genome and whole-exome sequencing in 3 Yemenite Jewish families segregating an atypical form of Usher syndrome, Khateb et al. (2018) identified a single shared homozygous 66- to 69.4-Mb region on chromosome 17.

Molecular Genetics

In 5 affected members of 3 consanguineous Yemenite Jewish families with an atypical form of Usher syndrome (618144), Khateb et al. (2018) identified homozygosity for a missense mutation in the ARSG gene (D45Y; 610008.0001). The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the families. All haplotypes surrounding the variant were identical, indicating that it is a founder mutation. The mutation was found in heterozygous state in 1 of 101 Yemenite Jewish controls, corresponding to a minor allele frequency of 0.005, and was not found in the gnomAD database.