Usher Syndrome Type 2 via the USH2A Gene

Usher syndrome is a clinically heterogeneous disorder characterized by progressive retinitis pigmentosa (RP) and sensorineural hearing impairment, with or without vestibular abnormalities. Three types are recognized based on the age of onset, severity of symptoms, and the vestibular involvement (Smith et al. Am J Med Genet 50:32-38, 1994). Usher syndrome type 2 (USH2 OMIM 276901) is characterized by mild to severe congenital hearing loss, RP with onset in the teens, and normal vestibular function. Features of RP include night blindness progressing to constriction of the peripheral visual field with eventual loss of central vision, abnormal fundus with bone-spicule deposits/attenuated retinal vessels, and abnormal electroretinographic (ERG) findings (Daiger et al. Arch Ophthalmol 125:151-158, 2007).

Usher syndrome type 2 (USH2) is a genetically heterogeneous autosomal recessive disease. Variants in three genes: USH2A, GPR98, and DFNB31 account for nearly all cases with detectable variants (Eudy et al. Science 280:1753-1757, 1998; Weston et al. Am J Hum Genet 74:357-366; Mburu et al. Nat Genet 34:421-428, 2003; Keats and Lentz, GeneReviews, 2009). Over 120 USH2A causative variants have been reported to date. The majority of variants are missense. Other variants include nonsense, splicing, and small insertions or deletions. Although most USH2A variants are private, a single nucleotide deletion (c.2299delG) predicted to result in a frameshift with premature termination codon, has been identified in several populations (Dreyer et al. Am J Hum Genet 69: 228–234, 2001). In addition to USH2, USH2A variants have been reported in patients with nonsyndromic autosomal recessive RP (AR-RP OMIM 608400) (Rivolta et al. Am J Hum Genet 66:1975-1978, 2000). The USH2A gene encodes usherin, which is involved in the development of the inner ear and eye.

This test allows the detection of variants in ~ 80% of patients with USH2 (Keats and Lentz, GeneReviews, 2009).

This test provides full coverage of all coding exons of the USH2A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.