Targeted Sequencing and Immunological Analysis Reveal the Involvement of Primary Immunodeficiency Genes in Pediatric IBD: a Japanese Multicenter Study

Suzuki, Tasuku; Sasahara, Yoji; Kikuchi, Atsuo; Kakuta, Humihiko; Kashiwabara, Toshihiko; Ishige, Takashi; Nakayama, Yoshiko; Tanaka, Masanori; Hoshino, Akihiro; Kanegane, Hirokazu; Abukawa, Daiki; Kure, Shigeo

doi:10.1007/s10875-016-0339-5

Cited by 29 publications

(33 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A better understanding of the genetic and immune defects of patients is critical to develop therapeutic strategies aimed at changing the clinical course of the disease and to guarantee an appropriate genetic counseling allowing the identification of PID patients before the onset of the disease (11)(12)(13). The application of Next Generation Sequencing (NGS) to PIDs has been a revolution and it has accelerated the discovery and identification of novel disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity (7,8,(14)(15)(16). Targeted gene-panel sequencing (17)(18)(19)(20)(21), whole exome sequencing (WES) (22,23) or whole genome sequencing (WGS) (24) approaches can rapidly identify candidate gene variants in an increasing number of genetically undefined diseases (17,24) and are widely used in several laboratories for the diagnosis of PIDs (10).…”

Section: Introductionmentioning

confidence: 99%

“…Nonetheless, delay in diagnosis can be caused by the huge amount of data retrieved from whole sequencing, increased costs sustained by clinical laboratories and the requirement of trained personnel to validate variants (7,8,22). An increased depth of the sequencing coverage is generally obtained using targeted gene panels, in favor of a high accuracy, amelioration of sensitivity and management of datasets, reducing the time of analysis, the costs and the interpretation of results, thus accelerating the diagnosis for the majority of PIDs (14,(16)(17)(18). On the other hand, the usefulness of targeted exome sequencing approach for the identification of PID patients has been demonstrated, with accurate detection of point mutations and exonic deletions in patients with either known or unknown genetic diagnosis (7,8).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

et al. 2019

View full text Add to dashboard Cite

Background: Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic immune disorders. While some PIDs can manifest with more than one phenotype, signs, and symptoms of various PIDs overlap considerably. Recently, novel defects in immune-related genes and additional variants in previously reported genes responsible for PIDs have been successfully identified by Next Generation Sequencing (NGS), allowing the recognition of a broad spectrum of disorders. Objective: To evaluate the strength and weakness of targeted NGS sequencing using custom-made Ion Torrent and Haloplex (Agilent) panels for diagnostics and research purposes. Methods: Five different panels including known and candidate genes were used to screen 105 patients with distinct PID features divided in three main PID categories: T cell defects, Humoral defects and Other PIDs . The Ion Torrent sequencing platform was used in 73 patients. Among these, 18 selected patients without a molecular diagnosis and 32 additional patients were analyzed by Haloplex enrichment technology. Results: The complementary use of the two custom-made targeted sequencing approaches allowed the identification of causative variants in 28.6% ( n = 30) of patients. Twenty-two out of 73 (34.6%) patients were diagnosed by Ion Torrent. In this group 20 were included in the SCID/CID category. Eight out of 50 (16%) patients were diagnosed by Haloplex workflow. Ion Torrent method was highly successful for those cases with well-defined phenotypes for immunological and clinical presentation. The Haloplex approach was able to diagnose 4 SCID/CID patients and 4 additional patients with complex and extended phenotypes, embracing all three PID categories in which this approach was more efficient. Both technologies showed good gene coverage. Conclusions: NGS technology represents a powerful approach in the complex field of rare disorders but its different application should be weighted. A relatively small NGS target panel can be successfully applied for a robust diagnostic suspicion, while when the spectrum of clinical phenotypes overlaps more than one PID an in-depth NGS analysis is required, including also whole exome/genome sequencing to identify the causative gene.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The mutation c.537G→A, which was observed in this patient, is the cause of VEOIBD, which develops 18-base deletion of the exon 4 of the IL-10RA protein and causes the impaired phosphorylation of STAT3 in peripheral blood mononuclear cell samples. 8,16 The changes in serum cytokines after influenza infection in our patient were highly affected by IL-10RA gene mutation.…”

Section: Discussionmentioning

confidence: 73%

“…After his death, we confirmed a homozygous and heterozygous mutation (c.537G→A) at the 3′ end of exon 4 of IL-10RA in the patient and his parents, respectively (Fig 2). 8 The IL-10 (65.1 pg/mL; reference: 0-7. 9 pg/mL) and IL-1A (76.…”

Section: Case Reportmentioning

confidence: 99%

IL-10RA Mutation as a Risk Factor of Severe Influenza-Associated Encephalopathy: A Case Report

et al. 2018

Self Cite

View full text Add to dashboard Cite

Influenza-associated encephalitis and encephalopathy (IAE) is a severe complication of influenza infection with high morbidity and mortality. We present the case of a patient with mutation who developed encephalopathy after influenza infection. A 10-day-old boy developed recurrent fever and anal fistula. Growth failure gradually became apparent. He had been treated with antibiotics and elemental nutrition. However, the patient did not respond to the treatments. At 11 months, he suddenly developed shock with encephalopathy and multiple organ failures. He was then diagnosed with IAE. A cytokine study revealed elevated levels of IL-1 receptor antagonist, IL-2, IL-6, IL-8, IP-10, eotaxin, G-CSF, MCP-1, and IL-10. These cytokines are normally downregulated by IL-10. Genetic testing revealed a mutation at the 3' end of exon 4 (c.537G→A). These findings might reflect an increased risk of severe IAE in patients with mutation.

show abstract

“…Because of the greatly reduced costs of next-generation sequencing, multiplex gene sequencing may be cost-effective, and can be used to detect causative genes. We previously identified PID-associated genes in 35 Japanese patients with pediatric-onset IBD [22], and 27 of these had VEOIBD. In this study, 55 genes that have been associated with PID and/or IBD were selected for targeted gene panel analysis (Table 3).…”

Section: Pathway Implicatedmentioning

confidence: 99%

Inflammatory bowel diseases and primary immunodeficiency diseases

Kanegane

2018

Immunological Medicine

Self Cite

View full text Add to dashboard Cite

Recent advances in molecular biology have provided important insights into the genetic background of various inflammatory diseases. In particular, genome-wide association studies of inflammatory diseases have revealed genetic loci that play critical roles in the pathology of inflammation. Whole-exome and whole-genome sequencing analyses have also identified more than 300 causative genes for primary immunodeficiency diseases (PIDs). Some genetic loci that are associated with inflammatory diseases are mutated in PIDs, suggesting close relationships between inflammation and PIDs. Inflammatory diseases for which genetic associations have been described include inflammatory bowel disease (IBD), multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus, and systemic lupus erythematosus. Herein, I discuss about the genetic interactions between IBD and PIDs. ARTICLE HISTORY

show abstract

Targeted Sequencing and Immunological Analysis Reveal the Involvement of Primary Immunodeficiency Genes in Pediatric IBD: a Japanese Multicenter Study

Cited by 29 publications

References 39 publications

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

IL-10RA Mutation as a Risk Factor of Severe Influenza-Associated Encephalopathy: A Case Report

Inflammatory bowel diseases and primary immunodeficiency diseases

Contact Info

Product

Resources

About