Arredondo-Vega et al. (2002) described a novel mutation in ADA, in 4 cases of delayed combined immunodeficiency, from 3 Saudi Arabian families.  Genotype analysis identified homozygosity for a novel splicing mutation; specifically, a T>A transversion at the final splice acceptor site in intron 11 of ADA.  This transversion converted a TG dinucleotide into AG, 13bp upstream of the normal AG splice acceptor site.  The resulting favored aberrant splicing added the 13nt intronic sequence between exon 11 and 12.  This altered the reading frame, which mutated the final 4 amino acids and extended the C-terminus by 43 residues.  This extension was determined to be the cause of ADA protein instability. In one family containing two affected siblings, somatic mosaicism through second site reversion was described in the eldest sibling (sib B).  Genotype analysis detected an 11nt deletion downstream of the transversion mutation, which inactivated the cryptic splice site and restored the normal splice acceptor site of intron 11-exon 12.

Hellani et al. (2009) described a novel mutation in ADA, in a 14 month old Saudi Arabian boy affected with SCID.  Multiple recurrent infections, and lymphopenia exhibiting a T-, NK-, and B- phenotype, lead to diagnosis of ADA-SCID.  DNA sequencing of ADA in the affected boy identified homozygosity for a novel hotspot missense mutation; specifically, a G>A transition in a CpG dinucleotide in exon 9 of ADA; The alteration of codon 282 from CGG to CAG replaced arginine with glutamine in the active domain of the ADA enzyme. The change in the hydropathy index, as well as protein analysis using software prediction programs -Protean and SIFT-, indicated an aberrant effect of the mutation on protein structure and function.  The boy was born to first-degree cousins both of whom were heterozygous for this mutation.  In addition, this mutation was screened against 50 controls of similar ethnicity, of whom none were carriers.  The boy underwent successful bone marrow transplantation using his HLA-identical sister as a donor.

Santisteban et al  (1995) described three new ADA mutations, two of which were identified in a Somali family.  One mutation was identified in a Somali child affected with ADA-SCID, and a second mutation was identified in the healthy father of the child.  The child was homozygous for a nonsense mutation; specifically, a C>T transition 7 base pairs after the translation start site of ADA.  The mutation (Q3X) converted glutamine (CAG) into a stop codon (TAG), resulting in premature termination of translation at codon 3.  The father was heterozygous for the Q3X mutation, with the second allele bearing a missense mutation exhibiting a non-pathogenic phenotype. The missense mutation (R142Q) involves a G>A transition at a CpG dinucleotide 425 base pairs after the translation start site, which converted arginine (CGA) to glutamine (CAA) at codon 142, and resulted in partially reduced enzyme activity.  Based on the high frequency of mutations in CpG hotspots in healthy individuals of African descent, the study suggests selection of CpA over the CpG hotspot during evolution of the ADA gene.

Sanchez et al  (2007) reported on 5 Somali cases with ADA-SCID, from 4 unrelated families in London, who were homozygous for a nonsense mutation (Q3X) in ADA.  Due to the established rarity of ADA-SCID, these cases prompted a study into the genetics of ADA in Somalis.  Based on a population of 207 unrelated Somali immigrants in Denmark, the frequency of the Q3X mutation was 1.2%; as none were homozygous for this mutation, 2.4% of individuals in this group were observed as carriers.  The incidence of ADA-SCID due to the Q3X mutation in Somalis was estimated at 1 in 5000-10,000 births. All individuals were part of the Hawiye clan -one of two largest clans- suggesting a higher incidence of ADA-SCID and a higher carrier frequency of Q3X in this subgroup.  Haplotype analysis incorporating 4 loci -the nonsense mutation (Q3X), 2 additional non-pathogenic missense mutations (K80R, R142Q), and a variable short tandem repeat region at an Alu element- identified a common haplotype, giving insight into common ancestry and the age of the Q3X mutation: Statistical analysis estimated the time to the most common ancestor to be 65,000 years (95% CI: 56,076-76,100 years).  The age of the Q3X mutation was estimated to be 7,100 years old (95% CI: 5,850-9375).