Submission Details

The PRPS1 gene has been associated with X-linked syndromic and non-syndromic hearing loss in at least 14 probands across 13 publications. Fourteen unique loss of function (LOF) missense variants have been reported in humans. Variants in this gene segregated with disease in more than 15 additional family members. PRPS1 was first associated with hearing loss in humans in 1988 (Becker et al.); however, since then LOF variants in this gene have also been associated with syndromic conditions in which hearing loss is a feature, including Charcot-Marie-Tooth disease (CMTX5), Arts Syndrome, and more severe deficiency disorders. Of note, intellectual disability and developmental delay are usually associated with Arts syndrome and more severe cases of PRPS1 deficiency, but not CMTX5 or nonsyndromic hearing loss (PMID: 24961627). While most males with Arts syndrome present with mild to moderate intellectual disability, females may have milder phenotypes. Additionally, visual and hearing impairment can make it difficult to assess cognitive ability. Because these conditions exist on a spectrum of severity, there may be significant overlap between phenotypes. There is some understanding of the mechanisms by which missense variants cause each disorder using structural analysis and crystal structures of the protein and its variants, but intrafamilial phenotypic variation makes it difficult to separate PRPS1 nonsyndromic and syndromic hearing loss. Loss of function variants have been found to cause nonsyndromic hearing loss, CMTX5 and Arts Syndrome, while PRPS1 superactivity disorders, which have been assessed separately, are caused by gain of function variants that destabilize allosteric sites (de Brouwer et al. 2010). In summary, PRPS1 is definitively associated with syndromic and nonsyndromic X-linked sensorineural hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was originally approved by the ClinGen Hearing Loss gene curation expert panel (GCEP) on 7/9/2018. The ClinGen ID/Autism GCEP reviewed the curation on 12/11/2019 to include additional information about the incidence of intellectual disability in the disease spectrum.