Screening for primary immunodeficiency diseases by next‐generation sequencing in early life

Sun, Jinqiao; Yang, Lin; Lu, Yulan; Wang, Huijun; Peng, Xiaomin; Dong, Xinran; Cheng, Guoqiang; Cao, Yun; Wu, Bingbing; Wang, Xiaochuan; Zhou, Wenhao

doi:10.1002/cti2.1138

Cited by 17 publications

(15 citation statements)

References 28 publications

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“…We previously showed that the combination of WES and CNVseq enables the diagnosis of rare neurological disorders ( Jiao et al., 2019 ). The current report indicates that NGS should also be recommended for those with undiagnosed immune abnormalities ( Sun et al., 2020 ; Zhang X. et al., 2020 ).…”

Section: Resultsmentioning

confidence: 94%

Disseminated Talaromyces marneffei Infection in a Non-HIV Infant With a Homozygous Private Variant of RELB

Ding

Huang

Zhao

et al. 2021

Front. Cell. Infect. Microbiol.

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ObjectiveThis study presents a relatively rare case of disseminated Talaromyces marneffei (T. marneffei) infection in an HIV-negative patient.MethodsAn 8-month-old girl was hospitalized because of uncontrollable fever and cough for 6 days. Routine laboratory tests, biochemical detection, immunological tests, pathogenic examination, and imaging inspection were performed. Genetic tests of trio whole genome sequencing (Trio-WES), trio copy number sequencing (Trio-CNVseq), and Sanger sequencing were conducted to identify pathogenic variants. In silico analysis of the sequence alignment and structural modeling results was carried out to study the possible pathogenicity of the identified variant. Western blotting was performed to investigate the expression of the identified gene at the protein level.ResultsEnhanced CT and MRI scanning demonstrated thymic dysplasia, diffuse pulmonary and liver nodules, and many balloon-like air sacs in both lungs. The white blood cell count, neutrophil count, and neutrophil ratio were normal or elevated. The patient was HIV-negative and bone marrow and blood culture showed T. marneffei infection. Total lymphocyte count, CD3+ T lymphocyte count, CD3+CD4+ T lymphocyte count, CD3+CD8+ T lymphocyte count, and NK cell count decreased, while the number of CD19 positive B cells increased. However, the ratio of CD3+CD4+:CD3+CD8+ T cells increased. Trio-WES identified a homozygous private variant of NM_006509: c.400_c.401insAGC/p.Lys134 delinsLysGln in RELB and Sanger sequencing validated the result. Structural modeling indicated that the variant may be pathogenic. Reverse transcription-polymerase chain reaction and Western blot analysis showed that the expression of RelB in the patient was lower than that in the healthy controls at mRNA and protein levels.ConclusionThis is the first report on disseminated T. marneffei infection in a patient with a homozygous private variant of RELB.

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Section: Resultsmentioning

confidence: 94%

Disseminated Talaromyces marneffei Infection in a Non-HIV Infant With a Homozygous Private Variant of RELB

Ding

Huang

Zhao

et al. 2021

Front. Cell. Infect. Microbiol.

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“…With the continued advancement of molecular technology, genome sequencing is becoming more common [ 37 ]. The resulting increasing numbers of medically actionable genotypes are driving the concept of “personalized medicine”.…”

Section: Discussionmentioning

confidence: 99%

“…The resulting increasing numbers of medically actionable genotypes are driving the concept of “personalized medicine”. As this technology advances, rare genotypes will be identified and known genotypes will be “immunophenotypically” expanded [ 37 ]. Soon, the complete genomes of newborns could be routinely sequenced [ 38 ], offering unprecedented insight into and foresight for a variety of health conditions including those of the immune system.…”

Section: Discussionmentioning

confidence: 99%

Growth in diagnosis and treatment of primary immunodeficiency within the global Jeffrey Modell Centers Network

Quinn

Modell

Orange

et al. 2022

Allergy Asthma Clin Immunol

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Background Primary immunodeficiencies (PI), which include more than 450 single-gene inborn errors of immunity and may affect up to 1% of the population, are genetic disorders that impair the immune system. If not properly identified and treated, individuals with PI are subject to serious, prolonged, and sometimes life-threatening infections or autoimmunity. Despite advancements, awareness of PI remains a critical issue for physicians and the public alike, as this leads to the enhanced and expedited management of these conditions. To address this critical issue, the Jeffrey Modell Foundation (JMF) formed a global network of specialized centers. The goal of this endeavor was to raise awareness of PI to better identify, diagnose, and treat patients, reducing associated mortality and morbidity and improving quality of life (QOL). For more than two decades, the Jeffrey Modell Centers Network (JMCN) has served as the foundation upon which these goals have been pursued. The JMCN currently includes 909 Expert Physicians at 400 institutions, in 316 cities, and 86 countries spanning six continents. Methods A survey was developed by JMF for members of the JMCN, following the most recent Classification of PI from the IUIS Expert Committee, to periodically describe the patient population, including treatment modalities and demographics. Physician-reported data from 2021 was compared to that from 2018 and 2013. Physicians in the JMCN also reported on select outcomes of their PI patients one year prior to and one year following diagnosis. Results A total of 300 JMF Physician Surveys from 681 physicians were included in this analysis. This is a 75% physician response rate. From 2013 to 2021, there was a 96.3% increase in patients followed in the US and an 86.1% increase globally. During the same period, patients identified with a specific PI defect increased by 46.6% in the US and 47.9% globally. Patients receiving IgG and HSCT increased by 110% and 201% respectfully since 2013. Early diagnosis led to reported decreased morbidity and mortality and reduced calculated healthcare costs. Conclusions This global analysis of physician-reported data on patients with PI demonstrates an increase in both diagnosed and treated patients. This substantial increase from within the JMCN is a testament to its impact. In addition to building an extensive global patient database, the expanding JMCN serves as a unique and critical resource, providing the infrastructure for earliest diagnosis, optimized treatments, and implementation of standard-of-care and best practices. The JMCN provides a critical platform that facilitates the education of physicians and patients, awareness initiatives, and research advances, through collaboration and connectivity, ultimately resulting in improved outcomes and QOL for patients with PI. The JMCN has steadily and substantially grown for more than two decades and continues to substantively impact the field of Immunology globally.

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“…In an HLH cohort, ES provided molecular explanation for 58% patients, which would have been underestimated if only a specific HLH gene-panel had been used [64]. ES conducted in 2392 newborns with abnormal lymphocyte counts or infections yielded a PIDD diagnosis in 51 patients (2.13%) and 68.6% of these patients were cured or improved their outcomes when having an early diagnosis [65].…”

Section: Genetic Diagnosis and Functional Validation Of Novel Ieimentioning

confidence: 99%

Functional Genetics in Inborn Errors of Immunity

Rey-Jurado

Poli

2021

Future Rare Dis.

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Inborn errors of immunity are genetic defects of the immune system, causing increased susceptibility to infection, autoinflammation, autoimmunity and immune dysregulation. Next-generation sequencing has enabled exponential identification of novel inborn errors of immunity due to mutations in genes encoding for proteins that participate in the immune response. However, genomic sequencing often yields multiple variants in potential candidate genes, hence functional validation of these genetic defects becomes paramount to achieve diagnosis and discovery. Genome-editing technologies such as CRISPR-Cas9 have allowed exponential advances on discovery of new primary immunodeficiencies, enabling appropriate diagnosis and treatment. This review summarizes the heterogeneous clinical presentation of primary immunodeficiencies and contextualizes the rationale for functional validation studies to achieve diagnosis and discovery, subsequently leading to the application of directed therapies.

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Screening for primary immunodeficiency diseases by next‐generation sequencing in early life

Cited by 17 publications

References 28 publications

Disseminated Talaromyces marneffei Infection in a Non-HIV Infant With a Homozygous Private Variant of RELB

Disseminated Talaromyces marneffei Infection in a Non-HIV Infant With a Homozygous Private Variant of RELB

Growth in diagnosis and treatment of primary immunodeficiency within the global Jeffrey Modell Centers Network

Functional Genetics in Inborn Errors of Immunity

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