scholarly journals The use of CRISPR for variant specificity in the genetic diagnosis of primary immunodeficiency disease (PID)

2019 ◽  
Author(s):  
Tiffeney Mann ◽  
Amy Smith ◽  
Sarah Spencer ◽  
Alasdair Russell ◽  
James Thaventhiran
Keyword(s):  
T Lymphocytes ◽  
Genetic Variants ◽  
Genetic Diagnosis ◽  
Primary Immunodeficiency Disease ◽  
Model Systems ◽  
Deficient Patient ◽  
Uncertain Significance ◽  
Immunodeficiency Disease ◽  
Variant Assessment ◽  
Generation Sequencing

ABSTRACTThe functional validation of genetic variants of uncertain significance (VUS) found in PID patients by next-generation sequencing has traditionally been carried out in model systems that are susceptible to artefact. We use CRISPR correction of primary human T lymphocytes to demonstrate that a specific variant in an IL-6R deficient patient is causative for their condition. This methodology can be adapted and used for variant assessment of the heterogeneous genetic defects that affect T lymphocytes in PID.

scholarly journals Characterization of a Cohort of Patients With LIG4 Deficiency Reveals the Founder Effect of p.R278L, Unique to the Chinese Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Xianze Luo ◽  
Qing Liu ◽  
Jinqiu Jiang ◽  
Wenjing Tang ◽  
Yuan Ding ◽  
...  
Keyword(s):  
Founder Effect ◽  
Genetic Diagnosis ◽  
Primary Immunodeficiency Disease ◽  
Chinese Patients ◽  
Mutation Site ◽  
Ligase Iv ◽  
Immunodeficiency Disease ◽  
Migration Pathways ◽  
Clinical Problems

DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by mutations in LIG4. Patients suffer from a broad spectrum of clinical problems, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and a predisposition to autoimmune diseases and malignancy. In this study, the clinical, molecular, and immunological characteristics of 15 Chinese patients with LIG4 deficiency are summarized in detail. p.R278L (c.833G>T) is a unique mutation site present in the majority of Chinese cases. We conducted pedigree and haplotype analyses to examine the founder effect of this mutation site in China. This suggests that implementation of protocols for genetic diagnosis and for genetic counseling of affected pedigrees is essential. Also, the search might help determine the migration pathways of populations with Asian ancestry.

scholarly journals B and T Lymphocytes in Primary Immunodeficiency Disease in Man

1973 ◽  
Vol 52 (4) ◽  
pp. 919-928 ◽  
Author(s):  
Kazimiera J. Gajl-Peczalska ◽  
Byung H. Park ◽  
W. Douglas Biggar ◽  
Robert A. Good
Keyword(s):  
T Lymphocytes ◽  
Primary Immunodeficiency ◽  
Primary Immunodeficiency Disease ◽  
Immunodeficiency Disease ◽  
B And T Lymphocytes

Chronic granulomatous disease due to different mutations in patients from the same consanguineous extended family

2018 ◽  
Vol 5 (2) ◽  
pp. 57-60
Author(s):  
Arnon Broides ◽  
Ronit Gavrieli ◽  
Jacov Levy ◽  
Rachel Levy ◽  
Nurit Hadad ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Primary Immunodeficiency ◽  
Genetic Diagnosis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Primary Immunodeficiency Disease ◽  
Genetic Mutation ◽  
Reasonable Assumption ◽  
Granulomatous Disease ◽  
Genetic Causes ◽  
Immunodeficiency Disease

Chronic granulomatous disease is a primary immunodeficiency disease caused by a genetic mutation in any of the 5 genes encoding the different components of the Nicotinamide Adenine Dinucleotide Phosphate reduced (NADPH)-Oxidase enzyme complex. Since primary immunodeficiency diseases are considered to be rare diseases, the genetic diagnosis of a certain primary immunodeficiency leads to the reasonable assumption that all patients with the same disease within the same family will have the same genetic mutation. We report 2 patients with chronic granulomatous disease from the same extended consanguineous family who had different genetic causes of their disease. Therefore, it is crucial to obtain a definitive genetic diagnosis of primary immunodeficiency disease even in patients from the same family, where the same genetic diagnosis is presumed to be the cause of the disease. Statement of novelty: Genetic causes of chronic granulomatous disease may be different in patients from the same family.

Siblings with Instability

2016 ◽  
Author(s):  
Richard A. Walsh
Keyword(s):  
Sanger Sequencing ◽  
Genetic Diagnosis ◽  
The Past ◽  
Powerful Approach ◽  
Uncertain Significance ◽  
Widespread Availability ◽  
Gene Panels ◽  
Underlying Pathophysiology ◽  
Generation Sequencing ◽  
Selection Of

Over the past 5 years, there has been a shift in the approach to searching for a genetic diagnosis in familial ataxic syndromes. Whereas in the past, a limited but expensive search through a selection of commercially available genes using Sanger sequencing was performed, there is now widespread availability of gene panels utilizing next-generation sequencing techniques. This is an efficient and powerful approach that may achieve a diagnosis in more than 30% of patients with a familial ataxia that remain undiagnosed. However, accurate phenotyping remains critical to allow interpretation of sequence variants of uncertain significance, to identify biomarkers that may be useful to monitor future therapies, and to assist with the identification of underlying pathophysiology.

scholarly journals Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic HLH disorders

2020 ◽  
Vol 4 (12) ◽  
pp. 2578-2594
Author(s):  
Vanessa Gadoury-Levesque ◽  
Lei Dong ◽  
Rui Su ◽  
Jianjun Chen ◽  
Kejian Zhang ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Clinical Phenotype ◽  
Genetic Diagnosis ◽  
Targeted Next Generation Sequencing ◽  
Disease Phenotypes ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Prf1 Gene ◽  
Generation Sequencing ◽  
Careful Thought

Abstract This article explores the distribution and mutation spectrum of potential disease-causing genetic variants in hemophagocytic lymphohistiocytosis (HLH)–associated genes observed in a large tertiary clinical referral laboratory. Samples from 1892 patients submitted for HLH genetic analysis were studied between September 2013 and June 2018 using a targeted next-generation sequencing panel approach. Patients ranged in age from 1 day to 78 years. Analysis included 15 genes associated with HLH. A potentially causal genetic finding was observed in 227 (12.0%) samples in this cohort. A total of 197 patients (10.4%) had a definite genetic diagnosis. Patients with pathogenic variants in familial HLH genes tended to be diagnosed significantly younger compared with other genes. Pathogenic or likely pathogenic variants in the PRF1 gene were the most frequent. However, mutations in genes associated with degranulation defects (STXBP2, UNC13D, RAB27A, LYST, and STX11) were more common than previously appreciated and collectively represented >50% of cases. X-linked conditions (XIAP, SH2D1A, and MAGT1) accounted for 17.8% of the 197 cases. Pathogenic variants in the SLC7A7 gene were the least encountered. These results describe the largest cohort of genetic variation associated with suspected HLH in North America. Merely 10.4% of patients were identified with a clearly genetic cause by this diagnostic approach; other possible etiologies of HLH should be investigated. These results suggest that careful thought should be given regarding whether patients have a clinical phenotype most consistent with HLH vs other clinical and disease phenotypes. The gene panel identified known pathogenic and novel variants in 10 HLH-associated genes.

scholarly journals Clinical Application of Metagenomic Next-Generation Sequencing for Suspected Infections in Patients With Primary Immunodeficiency Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjing Tang ◽  
Yu Zhang ◽  
Chong Luo ◽  
Lina Zhou ◽  
Zhiyong Zhang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Next Generation Sequencing ◽  
Primary Immunodeficiency ◽  
Primary Immunodeficiency Disease ◽  
Next Generation ◽  
Opportunistic Pathogens ◽  
Pathogen Identification ◽  
Conventional Methods ◽  
Immunodeficiency Disease ◽  
Generation Sequencing

BackgroundInfections are the major cause of morbidity and mortality in patients with primary immunodeficiency disease (PID). Timely and accurate microbiological diagnosis is particularly important in these patients. Metagenomic next-generation sequencing (mNGS) has been used for pathogen detection recently. However, few reports describe the use of mNGS for pathogen identification in patients with PID.ObjectiveTo evaluate the utility of mNGS for detecting pathogens in patients with PID, and to compare it with conventional microbiological tests (CMT).MethodsThis single center retrospective study investigated the diagnostic performance of mNGS for pathogens detection in PID patients and compared it with CMT. Sixteen PID patients with suspected infection were enrolled, and medical records were analyzed to extract detailed clinical characteristics such as gene variation, immune status, microbial distribution, time-consuming of mNGS and CMT, treatment, and outcomes.ResultsmNGS identified pathogenic microbe in 93.75% samples, compared to 31.25% for culture and 68.75% for conventional methods, and detected an extra 18 pathogenic microorganisms including rare opportunistic pathogens and Mycobacterium tuberculosis. Pathogen identification by mNGS required 48 hours, compared with bacterial culture for 3-7 days and even longer for fungus and Mycobacterium tuberculosis culture.ConclusionsmNGS has marked advantages over conventional methods for pathogenic diagnosis, particularly opportunistic pathogens and mixed infections, in patients with PID. This method might enable clinicians to make more timely and targeted therapeutic decisions, thereby improving the prognosis of these patients.

scholarly journals OP0102 GENE SCREENING OF PRIMARY IMMUNODEFICIENCY DISEASES IN PATIENTS WITH JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 66.2-66
Author(s):  
J. LI ◽  
W. Wang ◽  
C. Y. Wang ◽  
J. Y. Pan ◽  
H. Song
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Primary Immunodeficiency ◽  
Lupus Erythematosus ◽  
Gene Sequencing ◽  
Primary Immunodeficiency Disease ◽  
Type I ◽  
Cmv Infection ◽  
Systemic Lupus ◽  
Genetic Tests ◽  
Immunodeficiency Disease

Background:Systemic lupus erythematosus (SLE) is one of the most common auto-immune diseases in childhood. Primary immunodeficiency disease (PID) patients may present or combine with autoimmune diseases.Objectives:This study aimed to perform gene sequencing via high-throughput sequencing technology in a series of Chinese pediatric SLE patients, and investigate the concomitant situation of PIDs and SLE. Gene sequencing results may help clarify the pathogenesis of SLE.Methods:This was a retrospective case series of SLE children who referred to the Peking Union Medical College Hospital between 01/2016 and 09/2019. Genetic tests were performed in patients who met the inclusion criteria. We then collected demographic, clinical, and treatment information of all involved patients. Descriptive statistics were used.Results:Seventy-one patients were finally included (eighteen boys and fifty-three girls). The median age at the time of disease onset was 9.5 (range, 3-15) years. It is notable that five patients experienced their first attack before the age of five. Twenty-seven patients showed a persistent increase in ESR during treatment, while thirteen cases presented with repeated CMV infection, thirty-four cases with persistent low complement levels, seven with basal ganglia calcification showed in skull CT or MRI, four with special type of rash (i.e., frostbite-like rash, discoid erythema, reticular erythema), two with obvious hepatosplenomegaly, and one case with type I diabetes. Gene sequencing results showed that about ten patients combine with primary immunodeficiency disease, including Aicardi-Goutières Syndrome (AGS) (n=4), Spondyloenchondro-dysplasia with immune dysregulation (SPENCDI) (n=1), STING-associated vasculopathy with onset in infancy (SAVI) (n=1), lysinuric protein intolerance (LPI) (n=1), Ras-associated autoimmune leukoproliferative disorder (RALD) (n=2).Conclusion:SLE patients who present atypical or refractory manifestations should attach importance to the existence of primary immunodeficiency disease. Genetic tests are recommended for patients with early-onset SLE, especially those with recurrent frostbite-like rash or persistent CMV infection since childhood.References:[1]T Tarr, B Dérfalvi, N Győri, et al. Similarities and differences between pediatric and adult patients with systemic lupus erythematosus[J]. Lupus. 2015, 24: 796–803.[2]Gupta S, Louis A G. Tolerance and Autoimmunity in Primary Immunodeficiency Disease: a Comprehensive Review[J]. Clinical Reviews in Allergy & Immunology, 2013, 45(2):162-169.Disclosure of Interests:None declared

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