Publications by authors named "Kohsuke Imai"

173 Publications

Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency Patients: a Japanese Retrospective Study.

J Clin Immunol 2021 Aug 27. Epub 2021 Aug 27.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.

Purpose: Hematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID patients after HCT in Japan.

Methods: A cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974-2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP).

Results: The 10-year overall survival (OS) of the patients who received HCT in 2006-2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (n = 21) and matched sibling donors (n = 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006-2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8, P = 0.006), cytomegalovirus infection prior to HCT (HR: 9.4, P = 0.03), ≥ 4 months of age at HCT (HR: 25.5, P = 0.009), and mismatched UCB (HR: 19.8, P = 0.01).

Conclusion: We showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID.
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http://dx.doi.org/10.1007/s10875-021-01112-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390179PMC
August 2021

Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency.

J Allergy Clin Immunol Pract 2021 Oct 8;9(10):3767-3780. Epub 2021 Jul 8.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address:

Background: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment.

Objective: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT.

Methods: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed.

Results: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT.

Conclusions: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.
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http://dx.doi.org/10.1016/j.jaip.2021.05.045DOI Listing
October 2021

A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS.

Nat Immunol 2021 07 21;22(7):893-903. Epub 2021 Jun 21.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.
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http://dx.doi.org/10.1038/s41590-021-00951-zDOI Listing
July 2021

Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia.

Clin Immunol 2021 08 9;229:108776. Epub 2021 Jun 9.

Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4 T-cells, CD8 T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor β-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.
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http://dx.doi.org/10.1016/j.clim.2021.108776DOI Listing
August 2021

Therapeutic options for CTLA-4 insufficiency.

J Allergy Clin Immunol 2021 Jun 7. Epub 2021 Jun 7.

The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania.

Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness.

Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level.

Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated.

Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed.

Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
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http://dx.doi.org/10.1016/j.jaci.2021.04.039DOI Listing
June 2021

International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome.

J Allergy Clin Immunol 2021 May 24. Epub 2021 May 24.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).

Objectives: This study sought to characterize HCT outcomes in APDS.

Methods: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.

Results: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT.

Conclusions: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
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http://dx.doi.org/10.1016/j.jaci.2021.04.036DOI Listing
May 2021

Wiskott Aldrich Syndrome: A Multi-Institutional Experience From India.

Front Immunol 2021 16;12:627651. Epub 2021 Apr 16.

Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

Background: Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved awareness and better in-house diagnostic facilities at several centers in India has resulted in increased recognition of WAS. This study reports collated data across major primary immunodeficiency diseases (PID) centers in India that are involved in care of children with WAS and highlights the varied clinical presentations, genetic profile, and outcomes of patients in India.

Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with PID. Six centers provided requisite data that were compiled and analyzed.

Results: In this multi-institutional cohort, clinical details of 108 patients who had a provisional diagnosis of WAS were received. Of these, 95 patients with 'definite WAS' were included Fourteen patients were classified as XLT and 81 patients as WAS. Median age at onset of symptoms of patients was 3 months (IQR 1.6, 6.0 months) and median age at diagnosis was 12 months (IQR 6,48 months). Clinical profile included bleeding episodes (92.6%), infections (84.2%), eczema (78.9%), various autoimmune manifestations (40%), and malignancy (2.1%). DNA analysis revealed 47 variants in 67 cases. Nonsense and missense variants were the most common (28.4% each), followed by small deletions (19.4%), and splice site defects (16.4%). We also report 24 novel variants, most of these being frameshift and nonsense mutations resulting in premature termination of protein synthesis. Prophylactic intravenous immunoglobulin (IVIg) was initiated in 52 patients (54.7%). Hematopoietic stem cell transplantation (HSCT) was carried out in 25 patients (26.3%). Of those transplanted, disease-free survival was seen in 15 patients (60%). Transplant related mortality was 36%. Outcome details were available for 89 patients. Of these, 37% had died till the time of this analysis. Median duration of follow-up was 36 months (range 2 weeks- 12 years; IQR 16.2 months- 70 months).

Conclusions: We report the first nationwide cohort of patients with WAS from India. Bleeding episodes and infections are common manifestations. Mortality continues to be high as curative therapy is not accessible to most of our patients.
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http://dx.doi.org/10.3389/fimmu.2021.627651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086834PMC
September 2021

Case Report: Infantile-Onset Fulminant Type 1 Diabetes Mellitus Caused by Novel Compound Heterozygous Variants.

Front Immunol 2021 12;12:677572. Epub 2021 Apr 12.

Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.

Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a subtype of common variable immune deficiency (CVID). Numerous case reports and cohort studies have described a broad spectrum of clinical manifestations and variable disease phenotypes, including immune dysregulation, enteropathy, and recurrent infections. Although LRBA deficiency is an autosomal recessive primary immunodeficiency resulting in a phenotype similar to CVID, it is a monogenic disease and separate from CVID. Recently, in a report of monogenic primary immunodeficiency disorder associated with CVID and autoimmunity, the most common mutated gene was . We report the case of a girl who presented with fulminant type 1 diabetes at age 7 months. She later experienced recurrent bacterial infections with neutropenia and idiopathic thrombocytopenic purpura. Clinical genome sequencing revealed compound heterozygosity of the gene, which bore two novel mutations. A genetic basis should be considered in the differential diagnosis for very young patients with fulminant autoimmunity, and the diagnostic work-up should include evaluation of markers of immunodeficiency.
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http://dx.doi.org/10.3389/fimmu.2021.677572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072023PMC
April 2021

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India.

Front Immunol 2021 25;12:625320. Epub 2021 Feb 25.

Department of Pediatric Hematology and Oncology, Kanchi Kamakoti Child Trust Hospital, Chennai, India.

Background: Chronic granulomatous disease (CGD) is an inherited defect in phagocytic respiratory burst that results in severe and life-threatening infections in affected children. Single center studies from India have shown that proportion of autosomal recessive (AR) CGD is more than that reported from the West. Further, affected patients have high mortality rates due to late referrals and difficulties in accessing appropriate treatment. However, there is lack of multicentric collaborative data on CGD from India.

Objective: To describe infection patterns, immunological, and molecular features of CGD from multiple centers in India.

Methods: A detailed proforma that included clinical and laboratory details was prepared and sent to multiple centers in India that are involved in the care and management of patients with inborn errors of immunity. Twelve centers have provided data which were later pooled together and analyzed.

Results: Of the 236 patients analyzed in our study, X-linked and AR-CGD was seen in 77 and 97, respectively. Male female ratio was 172:64. Median age at onset of symptoms and diagnosis was 8 and 24 months, respectively. Common infections documented include pneumonia (71.6%), lymphadenitis (31.6%), skin and subcutaneous abscess (23.7%), blood-stream infection (13.6%), osteomyelitis (8.6%), liver abscess (7.2%), lung abscess (2.9%), meningoencephalitis (2.5%), splenic abscess (1.7%), and brain abscess (0.9%). Forty-four patients (18.6%) had evidence of mycobacterial infection. Results of molecular assay were available for 141 patients (59.7%)- (44.7%) gene defect was most common, followed by (31.9%), (14.9%), and (8.5%). While variants were documented only in Southern and Western parts of India, a common dinucleotide deletion in (c.835_836delAC) was noted only in North Indian population. Of the 174 patients with available outcome data, 67 (38.5%) had expired. Hematopoietic stem cell transplantation was carried out in 23 patients, and 12 are doing well on follow-up.

Conclusions: In India, proportion of patients with AR-CGD is higher as compared to Western cohorts, though regional differences in types of AR-CGD exist. Clinical profile and mortality rates are similar in both X-linked and AR-CGD. However, this may be a reflection of the fact that milder forms of AR-CGD are probably being missed.
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http://dx.doi.org/10.3389/fimmu.2021.625320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946827PMC
August 2021

Correction to: Helicobacter cinaedi-Associated Refractory Cellulitis in Patients with X-Linked Agammaglobulinemia.

J Clin Immunol 2021 May;41(4):847

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

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http://dx.doi.org/10.1007/s10875-021-01015-5DOI Listing
May 2021

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India.

Front Immunol 2020 8;11:619146. Epub 2021 Feb 8.

Institute of Child Health, Madras Medical College, Chennai, India.

Background: Severe Combined Immune Deficiency (SCID) is an inherited defect in lymphocyte development and function that results in life-threatening opportunistic infections in early infancy. Data on SCID from developing countries are scarce.

Objective: To describe clinical and laboratory features of SCID diagnosed at immunology centers across India.

Methods: A detailed case proforma in an Excel format was prepared by one of the authors (PV) and was sent to centers in India that care for patients with primary immunodeficiency diseases. We collated clinical, laboratory, and molecular details of patients with clinical profile suggestive of SCID and their outcomes. Twelve (12) centers provided necessary details which were then compiled and analyzed. Diagnosis of SCID/combined immune deficiency (CID) was based on 2018 European Society for Immunodeficiencies working definition for SCID.

Results: We obtained data on 277 children; 254 were categorized as SCID and 23 as CID. Male-female ratio was 196:81. Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively. Molecular diagnosis was obtained in 162 patients - (36), (26), (19), (17), (15), (13), (9), (3), (3), (2), (2), (2), (2), (2), (2), (2), (1), (1), (1), (1), (1), (1), and (1). Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%).

Conclusion: We document an exponential rise in number of cases diagnosed to have SCID over the last 10 years, probably as a result of increasing awareness and improvement in diagnostic facilities at various centers in India. We suspect that these numbers are just the tip of the iceberg. Majority of patients with SCID in India are probably not being recognized and diagnosed at present. Newborn screening for SCID is the need of the hour. Easy access to pediatric HSCT services would ensure that these patients are offered HSCT at an early age.
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http://dx.doi.org/10.3389/fimmu.2020.619146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897653PMC
June 2021

Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India.

Front Immunol 2020 15;11:612323. Epub 2021 Jan 15.

Department of Pediatric Hematology Oncology and Bone Marrow Transplant, Kanchi Kamakoti Childs Trust Hospital, Chennai, India.

Background: There is paucity of literature on XLA from developing countries. Herein we report the clinical and molecular profile and outcome in a multicenter cohort of patients with XLA from India.

Methods: Data on XLA from all regional centers supported by the Foundation for Primary Immunodeficiency Diseases (FPID), USA and other institutions providing care to patients with PIDs were collated. Diagnosis of XLA was based on European Society for Immunodeficiencies (ESID) criteria.

Results: We received clinical details of 195 patients with a provisional diagnosis of XLA from 12 centers. At final analysis, 145 patients were included (137 'definite XLA' and eight 'probable/possible XLA'). Median age at onset of symptoms was 12.0 (6.0, 36.0) months and median age at diagnosis was 60.0 (31.5, 108) months. Pneumonia was the commonest clinical manifestation (82.6%) followed by otitis media (50%) and diarrhea (42%). Arthritis was seen in 26% patients while 23% patients developed meningitis. Bronchiectasis was seen in 10% and encephalitis (likely viral) in 4.8% patients. was the commonest bacterial pathogen identified followed by , and . Molecular analysis revealed 86 variants in 105 unrelated cases. Missense variants in gene were the most common (36%) followed by frameshift (22%) and nonsense variants (21%). Most pathogenic gene variants (53%) were clustered in the distal part of gene encompassing exons 14-19 encoding for the tyrosine kinase domain. Follow-up details were available for 108 patients. Of these, 12% had died till the time of this analysis. The 5-year and 10-year survival was 89.9% and 86.9% respectively. Median duration of follow-up was 61 months and total duration of follow-up was 6083.2 patient-months. All patients received intravenous immunoglobulin (IVIg) replacement therapy. However, in many patients IVIg could not be given at recommended doses or intervals due to difficulties in accessing this therapy because of financial reasons and lack of universal health insurance in India. Hematopoietic stem cell transplant was carried out in four (2.8%) patients.

Conclusion: There was a significant delay in the diagnosis and facilities for molecular diagnosis were not available at many centers. Optimal immunoglobulin replacement is still a challenge.
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http://dx.doi.org/10.3389/fimmu.2020.612323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873890PMC
June 2021

Inherited CARD9 Deficiency in a Child with Invasive Disease Due to Exophiala dermatitidis and Two Older but Asymptomatic Siblings.

J Clin Immunol 2021 07 8;41(5):975-986. Epub 2021 Feb 8.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Science, Hiroshima, Japan.

Purpose: Autosomal recessive CARD9 deficiency predisposes patients to invasive fungal disease. Candida and Trichophyton species are major causes of fungal disease in these patients. Other CARD9-deficient patients display invasive diseases caused by other fungi, such as Exophiala spp. The clinical penetrance of CARD9 deficiency regarding fungal disease is surprisingly not complete until adulthood, though the age remains unclear. Moreover, the immunological features of genetically confirmed yet asymptomatic individuals with CARD9 deficiency have not been reported.

Methods: Identification of CARD9 mutations by gene panel sequencing and characterization of the cellular phenotype by quantitative PCR, immunoblot, luciferase reporter, and cytometric bead array assays were performed.

Results: Gene panel sequencing identified compound heterozygous CARD9 variants, c.1118G>C (p.R373P) and c.586A>G (p.K196E), in a 4-year-old patient with multiple cerebral lesions and systemic lymphadenopathy due to Exophiala dermatitidis. The p.R373P is a known disease-causing variant, whereas the p.K196E is a private variant. Although the patient's siblings, a 10-year-old brother and an 8-year-old sister, were also compound heterozygous, they have been asymptomatic to date. Normal CARD9 mRNA and protein expression were found in the patient's CD14 monocytes. However, these cells exhibited markedly impaired pro-inflammatory cytokine production in response to fungal stimulation. Monocytes from both asymptomatic siblings displayed the same cellular phenotype.

Conclusions: CARD9 deficiency should be considered in previously healthy patients with invasive Exophiala dermatitidis disease. Asymptomatic relatives of all ages should be tested for CARD9 deficiency. Detecting cellular defects in asymptomatic individuals is useful for diagnosing CARD9 deficiency.
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http://dx.doi.org/10.1007/s10875-021-00988-7DOI Listing
July 2021

Functional analysis of novel A20 variants in patients with atypical inflammatory diseases.

Arthritis Res Ther 2021 02 6;23(1):52. Epub 2021 Feb 6.

Department of Pediatrics, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.

Background: A20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by mutations in the TNFAIP3 gene, which encodes the protein A20. Numerous truncating mutations in the TNFAIP3 gene have been reported in HA20 patients, whereas fewer missense variants have had their pathogenicity confirmed. Here, we evaluated the pathogenic significance of three previously unreported missense variants of the TNFAIP3 gene in suspected cases of HA20.

Methods: We obtained the clinical features and immunological data of three patients with missense variants (Glu192Lys, Ile310Thr, and Gln709Arg) of unknown significance of TNFAIP3. We then performed in vitro functional assays including analysis of nuclear factor (NF)-κB reporter gene activity, detection of A20 expression and phosphorylation of A20 by IκB kinase β (IKKβ), and K63-deubiquitination assay using TNFAIP3-deficient HEK293 cells. Three known pathogenic missense mutations reported previously were also investigated.

Results: The inhibitory effect on NF-κB reporter gene activity was significantly disrupted by A20 Glu192Lys and the three known mutations. The variants Ile310Thr and Gln709Arg did not show a difference from the wild type in any of the assays performed in this study.

Conclusions: Among the three variants in the TNFAIP3 gene, Glu192Lys was interpreted as being likely pathogenic, but Ile310Thr and Gln709Arg as being not pathogenic (uncertain significance and likely benign, respectively), based on the American College of Medical Genetics and Genomics standards and guidelines. Our study highlights the necessity of performing in vitro functional assays, notably, NF-κB reporter gene assay, to evaluate the pathogenicity of TNFAIP3 missense variants for the accurate diagnosis of HA20.
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http://dx.doi.org/10.1186/s13075-021-02434-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866758PMC
February 2021

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

J Clin Immunol 2021 07 1;41(5):944-957. Epub 2021 Feb 1.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Purpose: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID).

Methods: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID.

Results: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival.

Conclusions: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.
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http://dx.doi.org/10.1007/s10875-021-00966-zDOI Listing
July 2021

Progressive Massive Splenomegaly in an Adult Patient with Kabuki Syndrome Complicated with Immune Thrombocytopenic Purpura.

Intern Med 2021 Jun 1;60(12):1927-1933. Epub 2021 Feb 1.

Department of Hematology/Oncology, Wakayama Medical University, Japan.

Kabuki syndrome is characterized by multiple systemic anomalies and intellectual disability. It is complicated with immunodeficiencies and autoimmune disorders. The syndrome is caused by a mutation in the KMT2D gene. We herein report a case of a Kabuki syndrome with developing immune thrombocytopenic purpura (ITP) and progressive splenomegaly. Laparoscopic splenectomy was performed and the patients' symptoms quickly disappeared with platelet recovery. After this operation, the patient had no severe complications. A sequence analysis of the KMT2D gene identified a pathogenic mutation frequently associated with ITP. Laparoscopic splenectomy is therefore considered to be a good therapeutic option for recurrent ITP and symptomatic splenomegaly with Kabuki syndrome.
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http://dx.doi.org/10.2169/internalmedicine.6694-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263171PMC
June 2021

Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3.

J Clin Immunol 2021 05 26;41(4):780-790. Epub 2021 Jan 26.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Purpose: Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients.

Methods: Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information.

Results: We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable.

Conclusion: Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.
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http://dx.doi.org/10.1007/s10875-021-00975-yDOI Listing
May 2021

A case of autoimmune enteropathy with CTLA4 haploinsufficiency.

Intest Res 2021 Jan 22. Epub 2021 Jan 22.

Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan.

Autoimmune enteropathy (AIE) is a rare disease, characterized by intractable diarrhea, villous atrophy of the small intestine, and the presence of circulating anti-enterocyte autoantibodies. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and mutations in FOXP3, which is a master gene of regulatory T cells (Tregs), are major causes of AIE. Recent studies have demonstrated that mutations in other Treg-associated genes, such as CD25 and CTLA4, show an IPEX-like phenotype. We present the case of a 13-year-old girl with CTLA4 haploinsufficiency, suffering from recurrent immune thrombocytopenic purpura and intractable diarrhea. We detected an autoantibody to the AIE-related 75 kDa antigen (AIE-75), a hallmark of the IPEX syndrome, in her serum. She responded well to a medium dose of prednisolone and a controlled dose of 6-mercaptopurine (6-MP), even after the cessation of prednisolone administration. Serum levels of the soluble interleukin-2 receptor and immunoglobulin G (IgG) were useful in monitoring disease activity during 6-MP therapy. In conclusion, autoimmune-mediated mechanisms, similar to the IPEX syndrome, may be involved in the development of enteropathy in CTLA4 haploinsufficiency. Treatment with 6-MP and monitoring of disease activity using serum levels of soluble interleukin-2 receptor and IgG is suggested for such cases.
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http://dx.doi.org/10.5217/ir.2020.00041DOI Listing
January 2021

Liver Abscess in Chronic Granulomatous Disease-Two Decades of Experience from a Tertiary Care Centre in North-West India.

J Clin Immunol 2021 04 2;41(3):552-564. Epub 2021 Jan 2.

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.

Purpose: Most of the literature on liver abscess in chronic granulomatous disease (CGD) emanates from developed countries. Data from developing countries are scarce. In this study, we report clinical features, microbiological profile, and treatment difficulties encountered while managing liver abscesses in patients with CGD at a tertiary care centre in North-West India.

Methodology: Case records of children with CGD and liver abscesses at Pediatric Immunodeficiency Clinic, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India were analyzed.

Results: Seven of 68 patients (10.29%) with CGD presented with hepatic abscess. One patient had 2 recurrences. All were males and age-range at presentation was 7 months-22 years. Mutation analysis was carried out in all patients-3 had defects in CYBB gene; 2 in NCF1; 2 in NCF2 gene. Staphylococcus aureus was isolated from 5 patients. Duration of antimicrobial treatment ranged from 3 weeks to 7 months. Open drainage was required in 1 patient, and 1 patient was treated with a prolonged course of prednisolone. Two children succumbed to the illness.

Conclusions: This is the largest reported experience of liver abscesses in patients with CGD from the developing world. Staphylococcus aureus was the commonest pathogen isolated. In our experience, prolonged courses of antimicrobials are usually necessary in these patients. Glucocorticoids can reduce inflammatory response and facilitate early resolution of abscesses in CGD.
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http://dx.doi.org/10.1007/s10875-020-00938-9DOI Listing
April 2021

Hemophagocytic Lymphohistiocytosis in Children with Chronic Granulomatous Disease-Single-Center Experience from North India.

J Allergy Clin Immunol Pract 2021 02 28;9(2):771-782.e3. Epub 2020 Nov 28.

Pediatric Allergy and Immunology Unit, Advanced Pediatrics Centre, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Background: Chronic granulomatous disease (CGD) is an inherited defect in components of the nicotinamide adenine dinucleotide phosphate oxidase complex that results in potential life-threatening infective and noninfective complications. Hemophagocytic lymphohistiocytosis (HLH) is an unusual but important inflammatory complication of CGD. Optimal management strategies have not yet been identified in children with CGD who develop HLH.

Objective: To analyze clinical and laboratory features of HLH in CGD from a tertiary-care center in North India.

Methods: A retrospective review of medical records of children with CGD diagnosed in the last 20 years was performed. Clinical and laboratory features of children with CGD who developed HLH were analyzed.

Results: Of 80 patients diagnosed with CGD, 5 (6.25%) had evidence of HLH. All 5 were males; 4 had X-linked CGD and 1 had autosomal recessive CGD (NCF2 defect). Two children with CGD had HLH as the predominant presenting manifestation mimicking the clinical presentation of congenital HLH. Infectious triggers identified were bloodstream infections (n = 3) (Candida albicans, Burkholderia cenocepacia, Francisella noatuensis), pneumonia (n = 4), and splenic abscess (n = 1). We document the first human infection with a fish pathogen, F. noatuensis, in a child with X-linked CGD. Although mortality was seen in 3 children who received only intravenous (IV) immunoglobulin therapy, the other 2 who received IV methylprednisolone pulse therapy survived.

Conclusion: HLH can be a presenting manifestation of CGD, and workup for CGD must be considered in children with HLH. Early recognition with optimal management of both infectious trigger and HLH is very important to prevent mortality.
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http://dx.doi.org/10.1016/j.jaip.2020.11.041DOI Listing
February 2021

Cytomegalovirus Laryngitis in Primary Combined Immunodeficiency Diseases.

J Clin Immunol 2021 01 8;41(1):243-247. Epub 2020 Oct 8.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

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http://dx.doi.org/10.1007/s10875-020-00873-9DOI Listing
January 2021

Helicobacter cinaedi-Associated Refractory Cellulitis in Patients with X-Linked Agammaglobulinemia.

J Clin Immunol 2020 11 10;40(8):1132-1137. Epub 2020 Sep 10.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

X-linked agammaglobulinemia (XLA) is characterized by severe or recurrent infections, hypogammaglobulinemia, and circulating B cell deficiency. The frequent pathogens seen in patients with XLA include Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and enterovirus as well as Campylobacter and Helicobacter species. Here, we describe two patients with XLA who developed cellulitis and bacteremia caused by Helicobacter cinaedi even when administered an appropriate immunoglobulin replacement therapy. H. cinaedi may be difficult to isolate using a conventional blood culture system and could be identified by sequence analysis and mass spectrometry. H. cinaedi infection causes recurrent symptoms frequently, and patients require a long course of antibiotic treatment. Recently, the case of non-H. pylori Helicobacter (NHPH) infection such as H. cinaedi and H. bilis infection is increasing in number in patients with XLA. Systemic NHPH infection should be suspected, and extensive microbiological analysis should be performed to appropriately treat patients with XLA who present with fever and skin lesions.
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http://dx.doi.org/10.1007/s10875-020-00830-6DOI Listing
November 2020

DNA Ligase IV Deficiency Identified by Chance Following Vaccine-Derived Rubella Virus Infection.

J Clin Immunol 2020 11 10;40(8):1187-1190. Epub 2020 Sep 10.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

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http://dx.doi.org/10.1007/s10875-020-00831-5DOI Listing
November 2020

Current Perspectives and Unmet Needs of Primary Immunodeficiency Care in Asia Pacific.

Front Immunol 2020 13;11:1605. Epub 2020 Aug 13.

Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

The Asia Pacific Society for Immunodeficiencies (APSID) conducted nine primary immunodeficiency (PID) Schools in 5 years since inauguration to provide PID care training for early career physicians in Asia Pacific, a region with divergent needs in PID resources and training. To identify differences in PID patient care resource and training needs across Asia Pacific and propose a corresponding action plan. The Human Development Index (HDI) indicates the degree of socio-economic development in each country/region. Information related to investigations and learning issues were extracted from the abstracts and personal statements from all Schools and mapped onto resource and training needs. Correlations between HDI and country/region-specific parameters were tested by two-tailed Pearson correlation. A total of 427 abstracts were received in nine Schools between 2015 and 2020, predominantly on immunodeficiencies affecting cellular and humoral immunity. Genetic confirmation was described in 61.8% of abstracts, and its absence negatively correlated with HDI ( = -0.696, = 0.004). Essential immunologic and genetic tests were not available in 25.4 and 29.5% of abstracts, respectively, and their absence negatively correlated with HDI ( = -0.788, < 0.001; = -0.739, = 0.002). HDI positively correlated with average testing level ( = 0.742, = 0.002). Cases from medium-HDI countries/regions focused on learning how to investigate a patient for PIDs in cases of severe or atypical infections, whereas those from very-high-HDI countries/regions, from which most faculty members originated, listed hematopoietic stem cell transplantation and gene therapy, newborn screening, and research as learning issues more frequently. There are unique HDI-related PID resource and training needs in each country/region. APSID proposes HDI group-specific strategies to improve PID care and education in her member countries/regions. Further quantitative analysis of needs in PID care in Asia Pacific is needed for lobbying governments to increase their support for PID care and research.
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http://dx.doi.org/10.3389/fimmu.2020.01605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438539PMC
April 2021

Hematopoietic Cell Transplantation for Chronic Granulomatous Disease in Japan.

Front Immunol 2020 29;11:1617. Epub 2020 Jul 29.

Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.

Hematopoietic cell transplantation (HCT) is established as a curative treatment for severe chronic granulomatous disease (CGD). However, outcomes of HCT for CGD in Japan had not been precisely reported. We evaluated the outcome of HCT for CGD in Japan by means of a nationwide survey. A total of 91 patients (86 males and 5 females) with CGD who received HCT between 1992 and 2013 was investigated. Their median age at HCT was 11 years (0-39). Sixty-four patients had X-linked CGD caused by CYBB gene mutations, 13 had autosomal recessive CGD (7 CYBA and 6 NCF2), and 14 were genetically undetermined. Seventy patients are still alive at a median follow-up of 38.9 (3.7-230) months. Three-year OS and EFS was 73.7 and 67.6%, respectively. Twenty-one patients died mainly from transplant-related mortality. The cumulative incidence of grade II to IV acute GVHD and extensive chronic GVHD was 27.2 and 17.9%, respectively. Risk factors for EFS after HCT for CGD were age >30 years ( < 0.01), non-CYBB gene mutations ( < 0.01) and CBT ( < 0.01). Regarding the reduced intensity conditioning (RIC) regimen, risk factors for EFS included anti-thymocyte globulin ( = 0.048) and not using low-dose irradiation therapy ( < 0.01), in addition to the preceding risk factors. We report outcomes of HCT for CGD in Japan. Future studies are needed to improve such outcomes, especially for patients harboring non-CYBB gene mutations and suffering from adult CGD. A RIC regimen including low-dose irradiation may be a good option to explore further.
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http://dx.doi.org/10.3389/fimmu.2020.01617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403177PMC
April 2021

Prospective Study of Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide and Antithymocyte Globulin from HLA-Mismatched Related Donors for Nonmalignant Diseases.

Biol Blood Marrow Transplant 2020 11 14;26(11):e286-e291. Epub 2020 Aug 14.

Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan; Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan. Electronic address:

Allogeneic hematopoietic stem cell transplantation (HSCT) is performed as a curative treatment for children with nonmalignant diseases, such as bone marrow failure syndromes and primary immunodeficiencies. Because graft-versus-host-disease (GVHD) is a major factor affecting survival probability and quality of life after HSCT, the availability of HLA-matched donors restricts the application of HSCT. Recently, HSCT with post-transplantation cyclophosphamide (PTCy) has emerged as a potent method to prevent GVHD after HSCT from HLA-haploidentical donors, and some studies have suggested the safety of PTCy-HSCT for nonmalignant diseases. We conducted a prospective clinical trial aiming to help confirm the safety of HSCT and further reduction of GVHD using a combination of PTCy and low-dose antithymocyte globulin (ATG) from HLA-mismatched related donors for children with nonmalignant diseases. Six patients underwent HSCT and achieved engraftment at a median of 14.5 days, and no patient developed severe acute GVHD. All patients had sustained donor chimerism without developing chronic GVHD at the last follow-up. In conclusion, HSCT with PTCy and low-dose ATG from an HLA-mismatched related donor were feasible to control GVHD for nonmalignant diseases in the children involved in our study. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.008DOI Listing
November 2020

Autosomal recessive complete STAT1 deficiency caused by compound heterozygous intronic mutations.

Int Immunol 2020 09;32(10):663-671

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

Autosomal recessive (AR) complete signal transducer and activator of transcription 1 (STAT1) deficiency is an extremely rare primary immunodeficiency that causes life-threatening mycobacterial and viral infections. Only seven patients from five unrelated families with this disorder have been so far reported. All causal STAT1 mutations reported are exonic and homozygous. We studied a patient with susceptibility to mycobacteria and virus infections, resulting in identification of AR complete STAT1 deficiency due to compound heterozygous mutations, both located in introns: c.128+2 T>G and c.542-8 A>G. Both mutations were the first intronic STAT1 mutations to cause AR complete STAT1 deficiency. Targeted RNA-seq documented the impairment of STAT1 mRNA expression and contributed to the identification of the intronic mutations. The patient's cells showed a lack of STAT1 expression and phosphorylation, and severe impairment of the cellular response to IFN-γ and IFN-α. The case reflects the importance of accurate clinical diagnosis and precise evaluation, to include intronic mutations, in the comprehensive genomic study when the patient lacks molecular pathogenesis. In conclusion, AR complete STAT1 deficiency can be caused by compound heterozygous and intronic mutations. Targeted RNA-seq-based systemic gene expression assay may help to increase diagnostic yield in inconclusive cases after comprehensive genomic study.
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http://dx.doi.org/10.1093/intimm/dxaa043DOI Listing
September 2020

Whole-Exome Sequencing-Based Approach for Germline Mutations in Patients with Inborn Errors of Immunity.

J Clin Immunol 2020 07 6;40(5):729-740. Epub 2020 Jun 6.

Department of Pediatrics, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Purpose: Owing to recent technological advancements, using next-generation sequencing (NGS) and the accumulation of clinical experiences worldwide, more than 420 genes associated with inborn errors of immunity (IEI) have been identified, which exhibit large genotypic and phenotypic variations. Consequently, NGS-based comprehensive genetic analysis, including whole-exome sequencing (WES), have become more valuable in the clinical setting and have contributed to earlier diagnosis, improved treatment, and prognosis. However, these approaches have the following disadvantages that need to be considered: a relatively low diagnostic rate, high cost, difficulties in the interpretation of each variant, and the risk of incidental findings. Thus, the objective of this study is to review our WES results of a large number of patients with IEI and to elucidate patient characteristics, which are related to the positive WES result.

Methods: We performed WES for 136 IEI patients with negative conventional screening results for candidate genes and classified these variants depending on validity of their pathogenicity.

Results: We identified disease-causing pathogenic mutations in 36 (26.5%) of the patients which were found in known IEI-causing genes. Although the overall diagnostic rate was not high and was not apparently correlated with the clinical subcategories and severity, we revealed that earlier onset with longer duration of diseases were associated with positive WES results, especially in pediatric cases.

Conclusions: Most of the disease-causing germline mutations were located in the known IEI genes which could be predicted using patients' clinical characteristics. These results may be useful when considering appropriate genetic approaches in the clinical setting.
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http://dx.doi.org/10.1007/s10875-020-00798-3DOI Listing
July 2020
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