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The following is a summary of “Evolving spectrum of adenosine deaminase (ADA) deficiency: Assessing genotype pathogenicity according to expressed ADA activity of 46 variants,” published in the August 2024 issue of Allergy and Immunology by Santisteban et al. 

Adenosine deaminase (ADA) deficiency shows significant clinical and genetic variability, with screening methods identifying asymptomatic infants whose conditions may involve ADA variants of unknown significance. 

Researchers conducted a retrospective study to assess the pathogenic potential of rare ADA missense variants and their relationship to RBC deoxyadenosine nucleotide (dAXP) content and phenotype. 

They expressed 46 ADA missense variants in the ADA-deficient SØ3834 strain of Escherichia coli, and defined genotypes categories (GCs) from I to IV based on ADA activity. They analyzed the relationships among GC rank, RBC total dAXP, and phenotype in 58 patients with 50 different genotypes, using the GC ranking to benchmark AlphaMissense for variant pathogenicity and a minigene assay to identify splicing variants in ADA exon 9. 

The results showed that the 46 missense variants expressed ∼0.001% to ∼70% of wild-type ADA activity, with 40% having <0.05% and 50% expressing >1%. RBC total dAXP ranged from undetectable to >75% of total adenine nucleotides and correlated well with phenotype. Both RBC dAXP and clinical severity were inversely related to total ADA activity expressed by inherited variants. The GC scoring system outperformed AlphaMissense in assessing variant pathogenicity, particularly for less deleterious variants. 

The study concluded that pathogenicity in ADA deficiency varies with total ADA activity, but for patients with indeterminate phenotypes, RBC total dAXP may offer better prognostic value than GC rank. 

Source: jacionline.org/article/S0091-6749(24)00864-9/fulltext