Background/Purpose: Patients with early-onset immunodysregulation, endocrinopathy and enteropathy but without identified mutations in FOXP3 are termed “IPEX-like,” and undergo trial-and-error immunosuppressive treatment with highly variable outcomes. The scope of genetic variation in these patients has not been well studied, even though genetic diagnosis can be critical to determining appropriate medical treatment.

We sought to investigate the prevalence and breadth of genetic diagnoses in patients with early-onset immune dysregulation, polyendocrinopathy, and/or enteropathy who had previously normal FOXP3 sequencing, in order to determine the clinical utility of broad panel sequencing in these patients.

Methods: Patients with IPEX-like disease who were referred from around the world for analysis of FOXP3 but who had apparently normal sequencing were re-evaluated using an extensive targeted sequencing panel encompassing 464 genes associated with innate disorders of immunity. Prediction pipelines were used to identify potentially damaging mutations, including copy number variants (CNVs) and splice site alterations, which were validated by whole genome sequencing (WGS) and RT-PCR, respectively.

Results: A likely genetic diagnosis was identified in 59 of 131 (44%) patients. Seven patients were found to have FOXP3 mutations not previously detected. Likely damaging variants in alternative genes were identified in 52 of the 124 (42%) remaining patients with intact FOXP3. Twenty-one patients had variants in genes known to cause IPEX-like Syndrome. The remaining genes belong to a wide array of phenotypic categories and biologic pathways. Within the patients carrying a known or candidate gene, over 75% had diagnoses which would have significantly altered therapeutic recommendations.

Conclusion: Patients with severe and early-onset immune dysregulation, polyendocrinopathy and/or enteropathy but without FOXP3 mutations (IPEX-like syndrome) have a high mutational burden with a very high rate of clinically actionable findings. These patients should undergo broad genetic screening for innate diseases of immunity, with technologies capable of detecting coding variants, splice-site variants, and CNVs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-diagnosis-of-childhood-immunodysregulation-endocrinopathy-and-enteropathy-x-linked-ipex-like-syndrome-and-implications-for-clinical-management/