The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutation

Abstract Background: Loss-of-function (LOF) mutation in signal transducer and activator of transcription 3 (STAT3) was one of the causes of the hyper immunoglobulin E (IgE) syndrome (HIES), while gain-of-function mutation (GOF) in STAT3 leads to immune dysregulation diseases. We retrospectively report 11 LOF STAT3 patients and 1 GOF STAT3 patient and illustrate their onset age, common clinical symptoms, immunologic and molecular manifestation. Methods: 12 patients were enrolled in our study. Serum immunoglobulins, lymphocyte subset detection and whole-exome sequencing were performed. Results: The median onset age of STAT3-deficient patients was 1.89 years. Eczema, recurrent respiratory infection, apparent fever, abscesses and Staphylococcus aureus infection was the classical manifestation. Elevated serum IgE level is not entirely unanimous with high eosinophils counts. Moderate viral DNA was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common spot, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients obtained a notable improvement after received intravenous immunoglobulin (IVIG). Conclusion: We believe IVIG may help reduce the opportunity of infection in STAT3-deficient patients. Significant variance at onset age probably is a great challenge for clinicians and urgently needs early diagnosis and treatment.

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CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz103 ◽

2019 ◽

Vol 25 (11) ◽

pp. 1788-1795 ◽

Cited By ~ 8

Author(s):

Thomas Magg ◽

Anna Shcherbina ◽

Duran Arslan ◽

Mukesh M Desai ◽

Sarah Wall ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Mononuclear Cells ◽

Severe Disease ◽

Effector Memory ◽

Loss Of Function ◽

Peripheral Blood Mononuclear ◽

Whole Exome ◽

Inflammatory Bowel

Abstract Background Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. Methods To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. Results Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. Conclusion Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

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The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations

10.21203/rs.3.rs-21778/v2 ◽

2020 ◽

Author(s):

Li Lin ◽

Ying Wang ◽

Bijun Sun ◽

Luyao Liu ◽

Wenjing Ying ◽

...

Keyword(s):

Mononuclear Cells ◽

Clinical Symptoms ◽

Current Knowledge ◽

Elevated Serum ◽

Age At Diagnosis ◽

Chinese Patients ◽

Common Mutation ◽

Novel Mutations ◽

Mutation Site ◽

Stat3 Mutations

Abstract Background: Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation.Methods: Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed.Results: The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin. Conclusion: We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.

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The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations

Allergy Asthma & Clinical Immunology ◽

10.1186/s13223-020-00462-w ◽

2020 ◽

Vol 16 (1) ◽

Author(s):

Li Lin ◽

Ying Wang ◽

Bijun Sun ◽

Luyao Liu ◽

Wenjing Ying ◽

...

Keyword(s):

Mononuclear Cells ◽

Clinical Symptoms ◽

Current Knowledge ◽

Elevated Serum ◽

Age At Diagnosis ◽

Chinese Patients ◽

Common Mutation ◽

Novel Mutations ◽

Mutation Site ◽

Stat3 Mutations

Abstract Background Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation. Methods Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed. Results The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin. Conclusion We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.

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The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations

10.21203/rs.3.rs-21778/v3 ◽

2020 ◽

Author(s):

Li Lin ◽

Ying Wang ◽

Bijun Sun ◽

Luyao Liu ◽

Wenjing Ying ◽

...

Keyword(s):

Mononuclear Cells ◽

Clinical Symptoms ◽

Current Knowledge ◽

Elevated Serum ◽

Age At Diagnosis ◽

Chinese Patients ◽

Common Mutation ◽

Novel Mutations ◽

Mutation Site ◽

Stat3 Mutations

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Hepatitis G Viral RNA in Serum and in Peripheral Blood Mononuclear Cells and Its Relation to HCV-RNA in Patients with Clotting Disorders

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656069 ◽

1997 ◽

Vol 77 (05) ◽

pp. 0868-0872 ◽

Cited By ~ 12

Author(s):

Li Sheng ◽

Ann Soumillion ◽

Kathelijne Peerlinck ◽

Chris Verslype ◽

Lan Lin ◽

...

Keyword(s):

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Elevated Serum ◽

Normal Serum ◽

Hcv Rna ◽

Peripheral Blood Mononuclear ◽

Hepatitis G Virus ◽

Blood Mononuclear Cells ◽

Hepatitis G

SummaryThe hepatitis G virus (HGV) has recently been identified as a new member of the Flaviviridae family. Infection by this virus is thought to be associated with blood borne hepatitis. In this study, the presence of HCV- and HGV-RNAs in serum or plasma (175 patients) and in peripheral blood mononuclear cells (PBMC) (133 patients) was investigated in patients with clotting disorders using a sensitive reverse transcriptase polymerase chain reaction (RT-PCR). HGV-RNA was detected in serum of 26 patients (14.8%). In apparently healthy blood donors, serum HGV-RNA was detected in 4 of 358 individuals investigated (1.12%). Ninety two percent of the 26 serum HGV-RNA positive patients had coinfection with the hepatitis C virus (HGV), especially with HCV genotype lb, the most common genotype in Belgium. Of these coinfected patients, 15 (62.5%) showed elevated serum ALT levels. Two patients who were solely infected with HGV had normal serum ALT. HGV-RNA in PBMC was found in 18 patients, of whom 3 were negative for serum HGV-RNA. As in case of HCV, HGV-RNA in PBMC is preferentially sensitive to interferon treatment. Nevertheless, rapid reappearance of HGV-RNA in PBMC was observed after cessation of treatment. In one patient, persistent serum ALT elevation seems to be associated with continued HGV viremia, despite the disappearance of serum HCV-RNA.

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Detection and Functional Evaluation of −262A/T and −188A/G Polymorphisms of SLAM Gene in Patients with Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.091390 ◽

2010 ◽

Vol 37 (11) ◽

pp. 2268-2272 ◽

Cited By ~ 3

Author(s):

YI YOU ◽

ZHE WANG ◽

GUO-HONG DENG ◽

YI LIU ◽

FEI HAO

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Mononuclear Cells ◽

Gene Promoter ◽

Chinese Patients ◽

Luciferase Reporter ◽

Functional Evaluation ◽

Reporter System ◽

Systemic Lupus ◽

Peripheral Blood Mononuclear

Objective.Signaling lymphocytic activation molecule (SLAM) has been related to the pathology of systemic lupus erythematosus (SLE) through regulation of T cell-dependent humoral immune responses. We investigated the functional associations of the −262A/T and −188A/G polymorphisms of SLAM in Chinese patients with SLE.Methods.Genotyping of −262A/T (rs2295614) and −188A/G (rs2295613) in SLAM was carried out in 248 cases and 278 controls. Promoter activities of haplotypes on the SLAM gene were evaluated with the dual-luciferase reporter system. The mRNA expressions of SLAM on peripheral blood mononuclear cells (PBMC) of SLE patients with different genotypes were determined by real-time polymerase chain reaction.Results.Frequencies of −262A allele and −188G allele were significantly higher in SLE patients than in controls. Haplotype analysis and multifactorial logistic regression analysis showed that individuals with the AG/AG haplotype had increased susceptibility to SLE (p = 0.002, OR 1.478, 95% CI 1.152–1.897). In response to PHA stimulation, the SLAM mRNA expression on PBMC of SLE patients was significantly higher in −262A-188G haplotype homozygotes compared with −262A-188G heterozygotes and individuals with other genotypes.Conclusion.Our findings suggest that −262A-188G haplotype in the SLAM gene promoter contributes to the risk of SLE by increasing the expression of SLAM.

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Increased Serum Interleukin 22 in Patients with Rheumatoid Arthritis and Correlation with Disease Activity

The Journal of Rheumatology ◽

10.3899/jrheum.111027 ◽

2012 ◽

Vol 39 (7) ◽

pp. 1320-1325 ◽

Cited By ~ 60

Author(s):

LAURINDO FERREIRA da ROCHA ◽

ÂNGELA LUZIA BRANCO PINTO DUARTE ◽

ANDRÉA TAVARES DANTAS ◽

HENRIQUE ATAÍDE MARIZ ◽

IVAN da ROCHA PITTA ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Mononuclear Cells ◽

Activity Index ◽

Elevated Serum ◽

Serum Levels ◽

Peripheral Blood Mononuclear ◽

Additional Tool ◽

Bone Erosions ◽

Interleukin 22

Objective.To analyze the role of interleukin 22 (IL-22) in rheumatoid arthritis (RA).Methods.IL-22 serum levels were measured in 83 patients with established RA under treatment with disease-modifying antirheumatic drugs and in 30 healthy controls matched for age and sex. Patients were assessed for clinical and laboratory variables. Correlations of IL-22 serum levels with disease activity measures [Clinical Disease Activity Index (CDAI) and Disease Activity Score for 28 joints (DAS28)], serological markers, bone erosions, and demographic factors were assessed. Peripheral blood mononuclear cells (PBMC) from 30 patients with RA and 14 controls were purified and stimulatedin vitrowith phorbol myristate acetate (PMA)/ionomycin. IL-22 production by PBMC and in serum was investigated by ELISA.Results.IL-22 levels were increased in patients with RA compared with controls (mean 432.37 pg/ml and 67.45 pg/ml, respectively; p < 0.001). Levels of IL-22 correlated with DAS28 and CDAI measures. Rheumatoid factor (RF) positivity was correlated with higher levels of IL-22 in patients with RA (mean 575.08 pg/ml; p = 0.001). The presence of bone erosions was associated with high IL-22 levels (p = 0.0001). PBMC stimulated with PMA/ionomycin expressed higher levels of IL-22 in patients with RA than controls but this was not significant (mean 584.75 pg/ml and 295.57 pg/ml; p = 0.553).Conclusion.IL-22 is elevated in the serum of patients with established RA. Elevated serum IL-22 allows discrimination between patients with different clinical and laboratory measures and indicates the potential of IL-22 as an additional tool for assessment of activity in RA, particularly in patients with RF antibodies and longterm disease. IL-22 is associated with bone-destructive disease.

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A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

10.21203/rs.3.rs-317232/v1 ◽

2021 ◽

Author(s):

Ying Zhang ◽

Yanyan Nie ◽

Yu Mu ◽

Jie Zheng ◽

Xiaowei Xu ◽

...

Keyword(s):

Intellectual Disability ◽

Mental Disorders ◽

De Novo ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

De Novo Mutation ◽

Loss Of Function ◽

Bioinformatics Analyses ◽

Whole Exome ◽

De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

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Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.745407 ◽

2021 ◽

Vol 13 ◽

Author(s):

Lin Sun ◽

Jianye Zhang ◽

Ning Su ◽

Shaowei Zhang ◽

Feng Yan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Symptoms ◽

Pathogenic Variants ◽

Dementia Patients ◽

Whole Exome ◽

Uncertain Significance ◽

Genetic Features ◽

Standards And Guidelines ◽

Degenerative Dementia

Background: Sporadic dementias generally occur in older age and are highly polygenic, which indicates some patients transmitted in a poly-genes hereditary fashion.Objective: Our study aimed to analyze the correlations of genetic features with clinical symptoms in patients with degenerative dementia.Methods: We recruited a group of 84 dementia patients and conducted the whole exome sequencing (WES). The data were analyzed focusing on 153 dementia-related causing and susceptible genes.Results: According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, we identified four reported pathogenic variants, namely, PSEN1 c.A344G, APP c.G2149A, MAPT c.G1165A, and MAPT c.G742A, one reported likely pathogenic variant, namely, PSEN2 c.G100A, one novel pathogenic variants, SQSTM1 c.C671A, and three novel likely pathogenic variants, namely, ABCA7 c.C4690T, ATP13A2 c.3135delC, and NOS3 c.2897-2A > G. 21 variants with uncertain significance in PSEN2, C9orf72, NOTCH3, ABCA7, ERBB4, GRN, MPO, SETX, SORL1, NEFH, ADCM10, and SORL1, etc., were also detected in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD).Conclusion: The new variants in dementia-related genes indicated heterogeneity in pathogenesis and phenotype of degenerative dementia. WES could serve as an efficient diagnostic tool for detecting intractable dementia.

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Anti-hepatitis G E2 Antibody Detection and Its Relation to Serum HGV-RNA in Patients with Clotting Disorders: High Prevalence of HGV Infection and Spontaneous Remission

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615059 ◽

1998 ◽

Vol 79 (04) ◽

pp. 752-755 ◽

Cited By ~ 5

Author(s):

L. Sheng ◽

A. Soumillion ◽

K. Peerlinck ◽

C. Verslype ◽

R. Schelstraete ◽

...

Keyword(s):

Mononuclear Cells ◽

Elevated Serum ◽

Spontaneous Remission ◽

Normal Serum ◽

Hcv Infection ◽

Antibody Detection ◽

Peripheral Blood Mononuclear ◽

High Prevalence

SummaryIn a previous study, we have determined the prevalence of serum HGV-RNA in patients with congenital clotting disorders. Twenty-six (15%) of 175 patients investigated were serum HGV-RNA positive. In addition, HGV-RNA was detectable in peripheral blood mononuclear cells (PBMC) in ten percent of the cases, three of these patients were serum HGV-RNA negative.In the present study, we have determined the prevalence of anti-HGV-E2 antibodies in the same patient population. Anti-HGV-E2 as determined by ELISA was detected in 45 patients (25.7%). Forty of these patients were serum HGV-RNA negative.Ninety-two percent of the 26 HGV viremic patients and all but one patient (44 patients) with detectable anti-HGV-E2 had coinfection with the hepatitis C virus (HCV). Of these coinfected patients, 62.5% of HGV viremic patients and 53% of anti-HGV-E2 positive patients showed elevated serum ALT levels. Anti-HGV-E2 seroconversion is thus not associated with HCV infection. Two patients who were solely infected with HGV had normal serum ALT levels. In a retrospective longitudinal study, we have observed in 15 patients that serum HGV-RNA persisted during one to 19 years of follow-up, while anti-HGV-E2 was repeatedly negative. Five additional patients who were anti-HGV-E2 positive with concomitant detectable HGV-RNA (4 patients in serum and 1 patient in PBMC) became HGV-RNA negative during follow-up, ranging from 1 to 8 years after the first detection of anti-HGV-E2 antibodies. Two patients had lost anti-HGV-E2 antibodies 3 to 6 years after the seroconversion without the re-appearance of serum HGV-RNA. From these findings, it is clear that the prevalence rate of HGV infection in patients with clotting disorders as determined by PCR assay for HGV-RNA and anti-HGV-E2 by ELISA is actually higher than the prevalence of HGV viremia. Although HGV viremia may persist for longer than 19 years, most of the patients infected with HGV may clear the viremia spontaneously. The clearance of viremia is usually associated with seroconversion to anti-HGVE2. In addition, anti-HGV-E2 may be lost during years of follow-up without the reappearance of the HGV-RNA. Although HGV infection does not seem to influence the fate of HCV infection and does not induce increased levels of serum ALT, the clinical significance of long-term infection remains to be established.

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