PNP was first reported in relation to autosomal recessive purine nucleoside phosphorylase deficiency in 1987 (Williams et al., PMID: 3029074). Purine nucleoside phosphorylase (PNP) deficiency is a defect in purine metabolism that causes severe combined immunodeficiency with typically profound T-cell deficiency and variable B-cell dysfunction. In addition to early-onset susceptibility to infection, those with PNP deficiency often also have neurological dysfunction which may include intellectual disability, increased or decreased muscle tone, spasticity, and/or ataxia. Some also have autoimmune dysfunction such as autoimmune hemolytic anemia. Hypouricemia is a biochemical sign of PNP deficiency. Heterozygotes are not known to be affected, though they may have decreased PNP enzyme activity.
Seven variants including missense, nonsense, frameshift, and splice site that have been reported in seven probands in seven publications are included in this curation (PMIDs: 3029074, 9737781, 22669887, 22578971, 34060650, 37328647, 38954121). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function.
This gene-disease relationship is also supported by functional assays and animal models (PMIDs: 1931007, 35641516, 9122228, 10859343). Deficiency of purine nucleoside phosphorylase causes an accumulation of the enzyme’s substrates including deoxyguanosine, which has known cell toxicity. Increased levels of apoptosis were observed in induced pluripotent stem cell‑derived neurons of PNP deficient patients. Multiple mouse models including three missense strains and one knockout mouse recapitulate the human phenotype of T cell deficiency.
In summary, there is definitive evidence supporting the relationship between PNP and autosomal recessive purine nucleoside phosphorylase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date June 19, 2025 (SOP Version 11).
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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