Submission Details

Adenosine deaminase deficiency in relation to severe combined immunodeficiency (SCID) was first reported in the 1970s, then in 1985 Bonthron et al. (PMID: 3839802) identified the first variant in ADA. The relationship of ADA to autosomal recessive adenosine deaminase deficiency was confirmed by the first report of biallelic variants from Akeson et al., 1987 (PMID: 3475710). ADA deficiency is associated with a cellular SCID phenotype that is low in T cells, B cells, and NK cells. ADA deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine deaminase-deficient severe combined immunodeficiency. Whilst most notable effects are on lymphocytes, other manifestations include skeletal abnormalities, neurodevelopmental effects and pulmonary manifestations associated with pulmonary-alveolar proteinosis. Affected SCID patients present in early infancy, usually with persistent infection, or with pulmonary insufficiency (reviewed in PMID: 29690908). However, there is heterogeneity in the phenotype of ADA-deficiency, with approximately 15–20% of patients exhibiting a delayed clinical onset, presenting with less severe combined immune deficiency later in life, hypomorphic variants are often identified in such patients. Additionally, healthy individuals with absence of ADA in erythrocytes but retention of readily detectable ADA in non-erythroid cells (partial ADA deficiency) have also been identified. Over 80 unique variants have been reported in humans (predominantly missense, as well as nonsense, frameshift, splicing, small indels, and gross deletions). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seventeen unique variants from 13 probands in 6 publications were curated (PMIDs: 29690908, 10200056, 7691348, 9225964, 9108404, 7599635). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. Experimentally, this gene-disease relationship is supported by its role in catalyzing the hydrolytic deamination of adenosine to inosine (PMID: 8452534), preventing accumulation of the cytotoxic metabolite deoxyadenosine, and its altered function in patient cells (PMID: 627115). Further support is provided by recapitulation of human disease in a mouse model (PMID: 9478961), as well as the rescue of the mouse model by either enzyme therapy (PMID: 10908569) or gene therapy (PMID: 16835374). Additionally, both enzyme therapy (PMID: 3807953) and gene therapy (PMID: 19179314) have shown rescue of the phenotype in patients. In summary ADA is definitively associated with autosomal recessive adenosine deaminase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.