Manish Butte

A functional assay to classify ZBTB24 missense variants of unknown significance.

March 31, 2020 By Manish Butte

A functional assay to classify ZBTB24 missense variants of unknown significance.

Hum Mutat. 2019 08;40(8):1077-1083

Authors: Wu H, Vonk KKD, van der Maarel SM, Santen GWE, Daxinger L

Abstract
Increasing use of next-generation sequencing technologies in clinical diagnostics allows large-scale discovery of genetic variants, but also results in frequent identification of variants of unknown significance (VUSs). Their classification into disease-causing and neutral variants is often hampered by the absence of robust functional tests. Here, we demonstrate that a luciferase reporter assay, in combination with ChIP-qPCR, reliably separates pathogenic ZBTB24 missense variants in the context of immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome from natural variants in healthy individuals and patients of other diseases. Application of our assay to two published ZBTB24 missense VUSs indicates that they are likely not to cause ICF2 syndrome. Furthermore, we show that rare gnomAD ZBTB24 missense variants in key residues of the C2H2-ZF domain lead to a loss of function phenotype that resembles ICF2, suggesting that these individuals are carriers of ICF syndrome. In summary, we have developed a robust functional test to validate missense variants in ZBTB24.

PMID: 31066130 [PubMed – indexed for MEDLINE]

Case Report: Exome Sequencing Reveals LRBA Deficiency in a Patient With End-Stage Renal Disease.

March 29, 2020 By Manish Butte

Case Report: Exome Sequencing Reveals LRBA Deficiency in a Patient With End-Stage Renal Disease.

Front Pediatr. 2020;8:42

Authors: Taylan C, Wenzel A, Erger F, Göbel H, Weber LT, Beck BB

Abstract
Background: Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency is characterized by autoimmunity, chronic diarrhea, and immunodeficiency. Minor renal manifestations have been found in a few patients, but kidney disease has not been systematically studied and may remain underdiagnosed in this highly variable entity. Results: Our patient initially presented with pancytopenia, enteropathy, hypogammaglobulinemia, and failure to thrive at the age of 15 months. Chronic kidney disease was diagnosed at 6 years. A renal biopsy taken at 11 years of age showed interstitial nephritis. The patient progressed rapidly to end-stage renal disease (ESRD) and underwent kidney transplantation at the age of 12 years. Bronchiolitis obliterans, post-transplant lymphoproliferative disease (PTLD), and chronic rejection complicated the post-transplant management. Graft loss required reinstitution of hemodialysis within 3 years. After negative results of different targeted sequencing strategies, exome sequencing identified a homozygous nonsense mutation (p.Q1010*) in the LRBA gene more than 21 years after the patient’s initial presentation. Conclusions: We report here the development of ESRD and long-term follow-up in a patient with LRBA deficiency. A molecular diagnosis in rare (kidney) disease like LRBA deficiency bears many advantages over a descriptive diagnosis. A precise diagnosis may result in improved (symptomatic) treatment and allows differentiating treatment- and procedure-related complications from manifestations of the primary disease.

PMID: 32219082 [PubMed – as supplied by publisher]

Upregulation of MYBL2 independently predicts a poorer prognosis in patients with clear cell renal cell carcinoma.

March 29, 2020 By Manish Butte

Upregulation of MYBL2 independently predicts a poorer prognosis in patients with clear cell renal cell carcinoma.

Oncol Lett. 2020 Apr;19(4):2765-2772

Authors: Sun SS, Fu Y, Lin JY

Abstract
MYB protooncogene-like 2 (MYBL2) is a transcription factor that is upregulated and significantly associated with various human cancer types. However, the potential role of MYBL2 in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated. Therefore, the expression and biological functions of MYBL2 in ccRCC were assessed in the current study using The Cancer Genome Atlas (TCGA). A Wilcoxon signed-rank test was performed to compare MYBL2 expression between ccRCC and normal tissues. Moreover, the association between MYBL2 expression and various clinicopathological factors was estimated using both the Wilcoxon signed-rank test and logistic regression. The differences in prognosis between patients with high- and low-MYBL2 expression were analyzed via the Kaplan-Meier method and Cox regression analysis. Finally, gene set enrichment analysis (GSEA) was performed to investigate the biofunctions of MYBL2 in ccRCC. It was revealed that MYBL2 was upregulated in ccRCC, and that the MYBL2 high-expression phenotype was significantly associated with sex, a high histological grade, an advanced clinical stage, tumor stage, lymph node metastasis, distant metastasis and poor overall survival (OS). It was also revealed, via the Cox regression analysis, that the upregulation of MYBL2 expression was able to independently predict a poor prognosis in patients with ccRCC. GSEA indicated that the intestinal immune network for IgA production, primary immunodeficiency, the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, the cytosolic DNA-sensing pathway, the p53 signaling pathway and the chemokine signaling pathway were all enriched in the high-MYBL2 expression datasets. In conclusion, the present findings indicate that MYBL2 may be used as an independent prognostic factor in patients with ccRCC.

PMID: 32218829 [PubMed – as supplied by publisher]

Asthma and allergic diseases are a phenotypic marker for CVID patients?

March 29, 2020 By Manish Butte

Asthma and allergic diseases are a phenotypic marker for CVID patients?

Ann Allergy Asthma Immunol. 2020 Mar 23;:

Authors: Fekrvand S, Abolhassani H, Delavari S, Yazdani R, Aghamohammadi A

PMID: 32217189 [PubMed – as supplied by publisher]

A case of aberrant CD8 T cell-restricted IL-7 signaling with a Janus kinase 3 defect-associated atypical severe combined immunodeficiency.

March 28, 2020 By Manish Butte

A case of aberrant CD8 T cell-restricted IL-7 signaling with a Janus kinase 3 defect-associated atypical severe combined immunodeficiency.

Immunol Res. 2020 Mar 25;:

Authors: Khanolkar A, Wilks JD, Liu G, Simpson BM, Caparelli EA, Kirschmann DA, Bergerson J, Fuleihan RL

Abstract
Severe combined immunodeficiency (SCID) disorders compromise lymphocyte numbers and/or function. One subset of SCID typically affects T cell and Natural Killer (NK) cell development in tandem (T-B+NK-) due to mutations arising in the genes encoding the common γ chain or Janus Kinase 3 (JAK3). In rare circumstances, mutations in the JAK3 gene have been reported to cause atypical SCID that selectively affects T cells (T-B+NK+). Here we describe a case involving a female infant who was referred to our institution on day nine of life following an abnormal newborn screen result for T-SCID. Immunological assessments revealed a T-B+NK+ phenotype and molecular analyses, including whole exome sequencing, identified compound heterozygous JAK3 variants (R117C and E658K). Pre-transplant phosflow analyses revealed a persistent IL-7 signaling defect, based on phospho-STAT5 measurements, only in CD8 but not CD4 T cells. Intriguingly, phospho-STAT5 signals in response to IL-2 stimulation were not affected in either CD4 or CD8 T cells. The pre-transplant clinical course was unremarkable, and the patient received a cord-blood stem cell transplant on day 716 of life. Post-transplant monitoring revealed that despite normalization of lymphocyte counts, the CD8 T cell-restricted IL-7 signaling defect was still evident at day 627 post-transplant (phospho-STAT5 signal in CD8 T cells was > 60% reduced compared with CD4 T cells). The post-transplant clinical course has also been complicated by identification of autoimmune responses and likely GVHD-induced ichthyosis. To the best of our knowledge, this report represents the third case of JAK3-associated atypical SCID reported in the literature.

PMID: 32215810 [PubMed – as supplied by publisher]

Weighted Gene Coexpression Network Analysis Identifies Specific Modules and Hub Genes Related to Major Depression.

March 28, 2020 By Manish Butte

Weighted Gene Coexpression Network Analysis Identifies Specific Modules and Hub Genes Related to Major Depression.

Neuropsychiatr Dis Treat. 2020;16:703-713

Authors: Zhang G, Xu S, Yuan Z, Shen L

Abstract
Purpose: Despite advances in characterizing the neurobiology of emotional disorders, there is still a significant lack of scientific understanding of the pathophysiological mechanisms governing major depressive disorder (MDD). This study attempted to elucidate the molecular circuitry of MDD and to identify more potential genes associated with the pathogenesis of the disease.
Patients and Methods: Microarray data from the GSE98793 dataset were downloaded from the NCBI Gene Expression Omnibus (GEO) database, including 128 patients with MDD and 64 healthy controls. Weighted gene coexpression network analysis (WGCNA) was performed to find modules of differentially expressed genes (DEGs) with high correlations followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to obtain further biological insight into the top three key modules. The protein-protein interaction (PPI) network, the modules from the PPI network, and the gene annotation enrichment of modules were analyzed, as well.
Results: We filtered 3276 genes that were considered significant DEGs for further WGCNA analysis. By performing WGCNA, we found that the turquoise, blue and brown functional modules were all strongly correlated with MDD development, including immune response, neutrophil degranulation, ribosome biogenesis, T cell activation, glycosaminoglycan biosynthetic process, and protein serine/threonine kinase activator activity. Hub genes were identified in the key functional modules that might have a role in the progression of MDD. Functional annotation showed that these modules primarily enriched such KEGG pathways as the TNF signaling pathway, T cell receptor signaling pathway, primary immunodeficiency, Th1, Th2 and Th17 cell differentiation, autophagy and RNA degradation and oxidative phosphorylation. These results suggest that these genes are closely related to autophagy and cellular immune function.
Conclusion: The results of this study may help to elucidate the pathophysiology of MDD development at the molecular level and explore the potential molecular mechanisms for new interventional strategies.

PMID: 32214815 [PubMed]

Management of osteoarticular fungal infections in the setting of immunodeficiency.

March 28, 2020 By Manish Butte

Management of osteoarticular fungal infections in the setting of immunodeficiency.

Expert Rev Anti Infect Ther. 2020 Mar 26;:

Authors: Papachristou SG, Iosifidis E, Sipsas NV, Gamaletsou MN, Walsh TJ, Roilides E

Abstract
Introduction: Osteoarticular fungal infections (OAFIs) complicate the clinical course of high-risk patients, including immunosuppressed individuals. Their management, however, despite being intricate, is governed by evidence arising from sub-optimal quality research, such as case series. Guidelines are scarce and when present result in recommendations based on low quality evidence. Furthermore, the differences between the management of immunocompromised and immunocompetent patients are not distinct. This is a narrative review after a literature search in PubMed, up to November 2019.Areas Covered: The major fungal groups causing osteomyelitis and/or arthritis are Candida spp., Aspergillus spp., non-Aspergillus filamentous fungi, non-Candida yeasts and endemic dimorphic fungi. Their epidemiology is briefly analyzed with emphasis on immunodeficiency and other risk factors. Management of OAFIs includes appropriate antifungal drug therapy (liposomal amphotericin B, triazoles or echinocandins), local surgery and immunotherapy for primary immunodeficiencies. Cessation of immunosuppressive drugs is also mandated.Expert Opinion: Management of OAFIs includes affordable and available options and approaches. However, research on therapeutic practices is urgently required to be further improved, due to the rarity of affected patients. Evolution is expected to translate into novel antifungal drugs, less invasive and precise surgical approaches and targeted enhancement of immunoregulatory pathways in defense of challenging fungal pathogens.

PMID: 32213145 [PubMed – as supplied by publisher]

Efficacy and safety of octanorm (cutaquig®) in adults with primary immunodeficiencies with predominant antibody deficiency: a prospective, open-label study.

March 28, 2020 By Manish Butte

Efficacy and safety of octanorm (cutaquig®) in adults with primary immunodeficiencies with predominant antibody deficiency: a prospective, open-label study.

Immunotherapy. 2020 Mar 26;:

Authors: Latysheva E, Rodina Y, Sizyakina L, Totolian A, Tuzankina I

Abstract
Aim: To evaluate efficacy and safety of octanorm (16.5% subcutaneous immunoglobulin) in adult patients with primary immunodeficiencies. Patients & methods: Primary immunodeficiencies patients (18-70 years) previously treated with intravenous immunoglobulin were included in this Phase III study. Octanorm was administered subcutaneously once weekly over 8 months. End points included infections, adverse events and quality of life. Results: 25 patients (mean age 35.2 years, female 60.0%) were recruited, 24 completed the study. Mean dose of octanorm was 0.11 g/kg/week. No serious bacterial infections occurred. Three patients (12.0%) had an adverse event (mild) assessed as related to octanorm. Both the mental and physical summary 36-item Short Form Health Survey scores were improved. Conclusion: Octanorm is effective, safe and improves quality of life. Clinical Trial registration number: NCT03988426.

PMID: 32212944 [PubMed – as supplied by publisher]

Persistent systemic rotavirus vaccine infection in a child with X-linked severe combined immunodeficiency.

March 27, 2020 By Manish Butte

Persistent systemic rotavirus vaccine infection in a child with X-linked severe combined immunodeficiency.

J Med Virol. 2019 06;91(6):1008-1013

Authors: Yoshikawa T, Ihira M, Higashimoto Y, Hattori F, Miura H, Sugata K, Komoto S, Taniguchi K, Iguchi A, Yamada M, Ariga T

Abstract
OBJECTIVE: The main aims of the present study were to elucidate the systemic group A rotavirus (RVA) infection and to clarify the genetic changes of persistent virus in the X-linked severe combined immunodeficiency (SCID) patient.
METHODS: RotaTeq vaccine (RV5) genotype-specific real-time reverse transcription polymerase chain reaction was used to monitor viral RNA load in serially collected serum and stool samples. Next-generation sequence analysis was used to determine the genotype of the virus by sequencing 11 gene segments. Polyacrylamide gel electrophoresis (PAGE) analysis was used to identify rearrangement of viral genes. The gene rearrangement was examined in NSP5 gene by using Sanger sequence.
RESULTS: A 7-month-old boy demonstrated chronic diarrhea following the third administration of RV5 and failure to thrive. He was diagnosed with X-linked SCID and successfully underwent cord blood transplantation. High copy numbers of RV5 genotype G1 RNA were detected in serially collected stool and serum samples and the kinetics of viral RNA loads were correlated with the degree of clinical disease. Next-generation sequence analysis revealed genetic reassortment at least between the strains WI79-9/G1P7[5] and WI79-4/G6P1A[8] in the VP7 gene and the VP4 gene among the vaccine-derived rotavirus strains. In addition, PAGE analysis suggested genetic rearrangements in several genes, and it was confirmed in the NSP5 gene by sequence analysis.
CONCLUSIONS: The kinetics of RVA RNA load in serum and stool samples was consistent with the clinical course of the patient. Among five genotypes of RV5 vaccine, G1 genotype replicated well in this patient. Reassortment and rearrangements were demonstrated in persistently infected G1 genotype of RV5.

PMID: 30687932 [PubMed – indexed for MEDLINE]

Hereditary Angioedema.

March 26, 2020 By Manish Butte

Hereditary Angioedema.

N Engl J Med. 2020 Mar 19;382(12):1136-1148

Authors: Busse PJ, Christiansen SC

PMID: 32187470 [PubMed – indexed for MEDLINE]