Retrospective Genetic Molecular Diagnosis for Inborn Errors of Immunity in Patients with Autoimmunity: Experience from a Single Center

Adults diagnosed with inborn errors of immunity (IEI) frequently lack a history of recurrent infections, but often present a myriad of autoimmune or inflammatory manifestations. Suspicion for an underlying IEI in patients with autoimmunity should be accounted for those patients with poly-autoimmunity (endocrinal or systemic or both), atypical course of disease, refractory immune cytopenias, and concurrent neoplasia or history of it. A recent work from Riviere et al. tested retrospectively a scoring system for diagnosis of IEI in a cohort of pediatric and adult patients. The most frequent warning sign among adults identified as high risk was bronchiectasia in the absence of cystic fibrosis, followed by systemic and endocrine autoimmune diseases, cytopenias, and more than 3 pneumonias. Case Patients Here, we present a case series of seven patients that were selected for molecular genetic testing. Among these patients, poly-autoimmunity, recalcitrant eczema, autoinflammatory clinical traits, immune cytopenias, atypical course and refractory disease were the main criteria for testing (Sanger, next-generation sequencing, whole exome sequencing). Results All seven patients presented IEI genetic variants of genes congruent with their disease profile. Patient characteristics and genetic results are depicted in Tables 1, 2. The most frequently diagnosed defect was common variable immune deficiency and immune dysregulation and autoinflammatory syndromes. Most of the variants found were not previously reported, of uncertain significance, and autosomal dominant in heritance. One patient had compound heterozygous likely pathogenic variants of AIRE gene, and one patient had a pathogenic variant of NOD2 gene. No patient had a history of recurrent infections. Table 1.Genetic testing of the seven patients.PatientGeneVariant (cDNA)EffectZygocityVariant typeMethodologyReportedACMG classification1AIRE1. c.1095+6G>A1. -Compound heterozygousGerminalSanger1. Yes1. LP2. c.834C>G2. p.S278_R2. No2. VUS21. CR21. c763C>T1. p.Arg255TrpHeterozygousGerminalTargeted NGS1. No1. VUS2. JAK32. c478G>T2. Gli160cis2. No2. VUS31. NOD21. C.2104C>T1. p.Arg702TrpHeterozygousGerminalTargeted NGS1. Yes1. P2. IL6ST2. c.371-3T>A2. IntrónicaHeterozygous2. No2. VUS3. MSN3. c.1304G>C3. p.Arg435ProHeterozygous3. No3. VUS4. PRKDC4. c9071C>T4. p.Pro3024LeuHeterozygous4. No4. VUS4CASP10c.738C>Ap.Asp246GluHeterozygousGerminalTargeted NGSNoVUS5NCKAP1Lc.2189C>Tp.Thr730MetHeterozygousGerminalTargeted NGSNoVUS61. ATP6AP11. c1219GzA1. p.Val407IleHeterozygousGerminalTargeted NGS1. No1. VUS2. LYST2. c4313C>G2. p.Ala1438GlyHeterozygousGerminalTargeted NGS2. No2. VUS3. TRFC3. c.1575C>G3. p.Asp525GluHeterozygousGerminalTargeted NGS3. No3. VUS4. IKZF34. c.707C>T4. p.Thr236IleHeterozygousGerminalWhole exome sequencing4. No4. VUS7PIK3CDc.707C>Tp.Pro236LeuHeterozygousGerminalWhole exome sequencingNoVUSIn bold, the genes mainly related to the patient’s phenotype. NGS: next-generation sequencing; LP: likely pathogenic; VUS: variant of uncertain significance; P: pathogenic.Table 2.Genetic, clinical, and phenotypical characteristics of the tested patients.PatientSexAgeGeneZygocityHeritanceFamily affectedClinical phenotypeT-B lymphocytes phenotypeIEI phenotype1F60AIRECompound heterozygousARNoPolyendocrinopathy + autoimmune hepatitis + celiac disease + undifferentiated spondyloarthropathy.CD4 - CD8 naive lymphopenia.Atypical autoimmune polyglandular syndromeB1a lymphopenia.2F621. CR2HeterozygousADNoLung granulomas.Bronchiectasia.CD4 - CD8 naive lymphopenia.NK deficit.CVID2. JAK3Heterozygous3F211. NOD2HeterozygousADNoRecurrent fever. Lymphoproliferation. Rash.Normal.Yao Syndrome2. IL6STHeterozygousAD3. MSNHeterozygousLX4. PRKDCHeterozygousAR4M30CASP10HeterozygousADNoALPS + psoriasis.CD4 - CD8 naive lymphopenia.CD8 early effectors elevated.B naive -pre-switch memory lymphopenia.ALPS5F65NCKAP1LHeterozygousAR?NoAutoimmune hepatitis + Sjögren’s syndrome.CD4 - CD8 naive lymphopenia.NK deficit.B lymphopenia: transitional, pre-post switch memory.CVID6F56IKZF3HeterozygousADYes (daughter)Panuveitis + IgA nephropathy.CD4 - CD8 naive lymphopenia.NK deficit.B lymphopenia: transitional.AIOLOS haploinsufficiency7M48PIK3CDHeterozygousVariableNoBehcet’s disease (skin, oral, neurological).Anti-phospholipid syndrome atypical epilepsy.Normal.Activated PIK3CD syndromeIn bold, the genes mainly related to the patient’s phenotype. F: female; M: male; AR: autosomal recessive; AD: autosomal dominant; ALPS: autoimmune lymphoproliferative syndrome; CVID: common variable immune deficiency. Conclusion Testing for IEI should be taken into account in patients with poly-autoimmunity, atypical manifestations, or refractory disease. A proper diagnosis of underlying IEI in this group could facilitate management and result in less morbidity for these patients.