The PRPS1 gene has been associated with X-linked phosphoribosylpyrophosphate synthetase superactivity using the ClinGen Clinical Validity Framework as of 7/5/2018. This association was made using case-level and experimental data. At least 9 unique gain of function (GOF) missense variants have been reported in humans. The PRPP protein was first associated with this disease in humans as early as 1972 (Sperling et al.); however, Roessler et al. first identified variants in the PRPS1 gene in 1993. Association is seen in at least 8 probands across 5 publications (PMID: 7593598, 28742244, 22246954, 8253776, 12847698). Variants in this gene segregated with disease in 1 additional family member (PMID: 28742244). The crystal structure of this enzyme has been solved, which informs that functionally assessed GOF missense variants are located in one of two allosteric sites in the protein (Chen et al. 2015). This gene-disease association is supported by functional assays demonstrating that PRPS1 variants cause an overproduction of pyrimidines, leading to hyperuricemia and gout (PMID: 7593598, 28742244, 23509005). Of note, intellectual disability and developmental delay are present in the severe superactivity phenotype, which is usually observed in infants or young children; in contrast, the mild phenotype normally lacks these conditions and manifests in juvenile or adult probands (PMID: 22246954, 28742244). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms between GOF missense variants in PRPS1-superactivity and PRPS1 deficiency disorders (X-linked nonsyndromic hearing loss, Charcot-Marie-Tooth disease, Arts syndrome, and more severe deficiency phenotypes), which are caused by loss of function missense variants. In summary, there is limited evidence to support this gene-disease association. Although additional case-level information is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. These classifications were approved by the ClinGen Hearing Loss Working Group 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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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