Usher Syndrome Type 2C and Deafness, Autosomal Recessive 57 (DFNB57) via the PDZD7 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. 1994). Usher syndrome type 2 (USH2) 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 eventually loss of central vision, abnormal fundus with bone-spicule deposits/attenuated retinal vessels, and abnormal electroretinographic (ERG) findings (Daiger et al. 2007). USH2C audiograms are slightly downsloping and show a moderate to severe hearing loss across all frequencies (Hilgert et al. 2009).

Usher syndrome type 2 (USH2) is a genetically heterogeneous autosomal recessive disease. Variants in three genes: USH2A, GPR98 (ADGRV1), and DFNB31 account for nearly all cases with detectable variants (Eudy et al. 1998; Weston et al. 2004; Mburu et al. 2003; Keats and Lentz 2010). PDZD7 is a homolog of genes causing USH1C and USH2D and encodes a binding protein that is expressed in the mechanosensory hair cells of the inner ear (Ebermann et al. 2010, Zou et al. 2014). Digenic inheritance of USH2C was reported in a single German individual with heterozygous frameshift variants in both GPR98 and PDZD7 (Ebermann et al. 2010). A different frameshift variant in PDZD7 was shown to increase the severity of retinal disease in patients with USH2A variants (Ebermann et al. 2010). PDZD7 was shown to interact with the Usher proteins GPR98 and USH2A in yeast-2-hybrid and coimmunoprecipitation studies, supporting the model of digenic inheritance of USH2C via variants in GPR98 and PDZD7 as well as the retinal disease modifying effect of variants in PDZD7 on patients with USH2A (Ebermann et al. 2010). Homozygosity for a balanced reciprocal translocation between the long arms of chromosomes 10 and 11 that disrupts PDZD7 transcripts was found to cause congenital bilateral moderate sensorineural hearing loss in a four year old boy. No RP or vestibular dysfunction was observed over the next five years, although development of RP later in life cannot be ruled out (Schneider et al. 2009).

Clinical sensitivity cannot be estimated because PDZD7 pathogenic variants have been documented in only a small number of patients with Usher syndrome or autosomal recessive nonsyndromic hearing loss.

This test provides full coverage of all coding exons of the PDZD7 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).