Similarly, additional tests for extremely rare genetic defects might be appropriate but are only available at specialized laboratories, often as part of research projects. The clinical utility of the algorithm to use a limited set of

laboratory tests to differentiate find more between conventional and monogenic VEOIBD, as suggested in Figure 2, is based on experience, case reports, and case series of individual disorders. It has not been validated in prospective studies of patients with all forms of VEOIBD. The classic approach to detect monogenic forms of IBD, as described in the preceding text and summarized in Figure 2, is based on careful phenotypic analysis and candidate sequencing to confirm a suspected genetic diagnosis. Due to the increasing number of candidate genes, sequential candidate

sequencing can be costly and time consuming. It is therefore not surprising to propose that this strategy of functional screening followed by genetic confirmation will increasingly be complemented by early parallel genetic screening using next-generation sequencing followed by functional confirmation. The US Food and Drug Administration has recently granted marketing authorization for the first next-generation genomic sequencer, which will further pave the way for genome, exome, or other targeted parallel genetic tests in routine practice.132 and 133 WES or even whole-genome sequencing will increasingly Ponatinib clinical trial become part of the routine analysis of patients with suspected genetic Compound C in vitro disorders including subtypes of IBD.59, 134 and 135 This has several important implications for selecting candidate gene lists, identification of disease-causing variants, and dealing with a large number of genetic variants of unknown relevance. In research and clinical settings, WES

has been shown to reliably detect genetic variants that cause VEOIBD in genes such as XIAP, 67IL10RA, 136 and 137G6PC3, 138MEFV, 59LRBA, 88FOXP3, 126 and TTC7A. 38 There are several reasons to propose extended parallel candidate sequencing for patients with suspected monogenic IBD. Immune and gastrointestinal phenotypes of patients evolve over time, whereas the diagnosis needs to be made at the initial presentation to avoid unnecessary tests and treatment. IBD-like immunopathology can be linked to nonclassic phenotypes of known immunodeficiencies, such as hypomorphic genetic defects in SCID patients (in genes such as ZAP70, RAG2, IL2RG, LIG4, ADA, DCLRE1C, CD3G, or TTC7A; see Table 2) with residual B- and T-cell development, 38, 81 and 82 glucose-6-phosphatase 3 deficiency with lymphopenia, 50 or FOXP3 defects without the classic IPEX phenotype. 126 WES has revealed unexpected known causative variants 67 even after workup in centers with specialized immunologic and genetic clinical and research facilities.