LAUSR

To the Editor: Adenosine deaminase (ADA) deficiency is an autosomal recessive disorder of purine metabolism that typically presents as a severe combined immunodeficiency in infancy (OMIM: 102700). Approximately 10–15% of patients have a delayed clinical onset (6–24 months) and a smaller proportion present later still (4 years to adulthood) with a milder phenotype and gradual immunological deterioration [1]. Despite the expanding application of modern genetic techniques, the diagnosis of primary immunodeficiencies (PIDs) can be difficult due to the ever-increasing phenotypic heterogeneity of these disorders [2]. Here, we report a case of lateonset ADA deficiency caused by two novel mutations. Both the clinical and genetic diagnoses were challenging and only achieved following the application of several molecular approaches. This case also illustrates the increasing importance of collaborative working between clinicians and laboratory diagnostic scientists. A 7-year-old girl was referred to the paediatric immunology clinic with a 12-month history of recurrent chest infections. She was previously reviewed by dermatologists for extensive molluscum contagiosum, which had been present for several years. Throughout early childhood, the patient was generally well and there were no concerns regarding her general health. She received all primary immunisations without complications. Other past medical history included a recent diagnosis of hypothyroidism requiring thyroxine replacement. The patient was of non-consanguineous white British ancestry, with no family history suggestive of a PID. She attended mainstream primary school and did not have any special education needs. Initial investigations showed normal levels of IgG and IgA and marginally elevated IgM. There was a lymphopenia affecting all subsets equally. T cell proliferation to phytohemagglutinin (PHA) was reduced but appeared normal to anti-CD3 (Supplementary Table E1). Specific antibody titres to tetanus, Haemophilus influenzae type b and pneumococcus, were within the protective range, suggesting previous adequate responses to vaccination. Interestingly, there were past records of the patient being lymphopenic (at least two CBCs in the last 18 months showing lymphopenia of 0.2 and 0.3 10*9/L (reference range 1.5–4.5)). A diagnosis of combined immunodeficiency was suspected, and molecular genetic investigations were performed on a panel of 37 PID-associated genes following clinical exome sequencing (see Supplementary Methods). Interrogation of these data identified the heterozygous missense variant, c.961G > A p.(Glu321Lys), in ADA exon 10 (NM_000022.3) (Supplementary Fig. E1), which was absent from population control cohorts (including gnomAD [3] and in-house databases) and highly conserved across vertebrate species. This prompted biochemical analysis of ADA activity, which showed the presence of dATP (245 μmol/L), dADP Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00625-4) contains supplementary material, which is available to authorized users.