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European Genetic Disease Diagnostics

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Advancing immunodeficiency diagnostic tools

The prompt and correct diagnosis of rare diseases is of paramount importance for appropriate management measures and treatment to avoid severe and irreversible complications. To this end, European researchers developed high-throughput methods for mutation analysis that will also shed light onto disease aetiology.


Primary immunodeficiencies (PIDs) are rare genetic disorders affecting about 1 in every 100 000 individuals or less. There is an estimated number of some 60 000 patients suffering from PIDs in Europe. Currently, mutations in 179 genes have been identified as causing PIDs. Therefore, mutation analysis is required in order to prevent the inheritance of these conditions. Obtaining correct diagnosis is, however, difficult, time-consuming and costly. To address these shortcomings, the EU-funded 'European genetic disease diagnostics' (EURO-GENE-SCAN) project aimed to develop high-throughput technologies for the diagnosis of PIDs in a more rapid and cost-effective manner. The scientific objectives of the consortium included adapting the DNA sequencing for PID-related genes, developing a specific single nucleotide polymorphism (SNP)-based chip, and optimising large-scale screening through reverse phase protein (RPP) microarrays. To amplify the genomic regions of interest for subsequent mutation analysis and sequencing, partners developed a DNA capture technology based on the hybridisation of oligonucleotide constructs, called 'selectors', to defined target nucleic acid sequences. The selectors contain target-complementary sequences, and act as ligation templates to direct the circularisation of target DNA fragments, which can then be amplified. This method was adapted to include the complete set of 156 PID genes as well as newly discovered genes. The chosen design used over 12 000 selectors that covered all potential mutations of the 179 PID-related genes. Analyses of patients with the antibody immunodeficiency CVID and their families revealed a mutation in TACI tumour necrosis factor receptor 13B (TNFRSF13B). Using genome-wide SNP arrays, the consortium identified a potential modifier locus mutated in patients and not in healthy family members. This locus contained genes implicated in TACI-downstream signalling. Large-scale screening for concentrations of serum proteins was another EURO-GENE-SCAN project objective. Measuring antibody and complement levels would find application in the diagnosis of patients with antibody deficiencies. To this end, the consortium developed bead-based technology that could quantify up to 100 proteins simultaneously. Implementation of the EURO-GENE-SCAN methodology could improve PID diagnosis and help explain the observed clinical heterogeneity of these conditions.

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