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

2020 ◽  
Vol 40 (5) ◽  
pp. 729-740 ◽  
Author(s):  
Tsubasa Okano ◽  
Kohsuke Imai ◽  
Takuya Naruto ◽  
Satoshi Okada ◽  
Motoi Yamashita ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Germline Mutations ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome

scholarly journals Whole-exome sequencing for detecting inborn errors of immunity: overview and perspectives

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2056
Author(s):  
Barbara Bosch ◽  
Yuval Itan ◽  
Isabelle Meyts
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Mechanisms ◽  
Future Research ◽  
Sequencing Analysis ◽  
Genetic Etiology ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome ◽  
Clinical Description

The study of inborn errors of immunity is based on a comprehensive clinical description of the patient’s phenotype and the elucidation of the underlying molecular mechanisms and their genetic etiology. Deciphering the pathogenesis is key to genetic counseling and the development of targeted therapy. This review shows the power of whole-exome sequencing in detecting inborn errors of immunity along five central steps taken in whole-exome sequencing analysis. In parallel, we highlight the challenges for the clinical and scientific use of the method and how these hurdles are currently being addressed. We end by ruminating on major areas in the field open to future research.

scholarly journals Whole exome sequencing in inborn errors of immunity

2017 ◽  
Vol 17 (6) ◽  
pp. 421-430 ◽  
Author(s):  
Giorgia Bucciol ◽  
Erika Van Nieuwenhove ◽  
Leen Moens ◽  
Yuval Itan ◽  
Isabelle Meyts
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome

scholarly journals A single‐center pilot study in Malaysia on the clinical utility of whole‐exome sequencing for inborn errors of immunity

2021 ◽  
Author(s):  
Adiratna Mat Ripen ◽  
Chai Teng Chear ◽  
Mohd Farid Baharin ◽  
Revathy Nallusamy ◽  
Kwai Cheng Chan ◽  
...  
Keyword(s):  
Pilot Study ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Utility ◽  
Single Center ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors

2021 ◽  
Author(s):  
Juan Chen ◽  
Yan Li ◽  
Jianlei Wu ◽  
Yakun Liu ◽  
Shan Kang
Keyword(s):  
Germ Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Copy Number ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Deletion Region ◽  
Whole Exome

Abstract Background Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. Methods The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes corresponding to copy number alterations (CNA) deletion and duplication region, functional annotation of was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region. Results In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YST). Moreover, POU5F1 was the most significant mutated gene with mutation frequency > 10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region) was found in 2 YST and nuclear staining in 2 dysgerminomas (DG) tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I-like receptor, Toll-like receptor, NF-kappa B and Jak–STAT. KRT4, RPL14, PCSK6, PABPC3 and SARM1 mutations were detected in both peripheral blood and tumor samples. Conclusions Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

scholarly journals Dose-dependent de novo germline mutations detected by whole-exome sequencing in progeny of ENU-treated male gpt delta mice

2016 ◽  
Vol 810 ◽  
pp. 30-39 ◽  
Author(s):  
Kenichi Masumura ◽  
Naomi Toyoda-Hokaiwado ◽  
Akiko Ukai ◽  
Yoichi Gondo ◽  
Masamitsu Honma ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Germline Mutations ◽  
Treated Male ◽  
Whole Exome ◽  
Dose Dependent ◽  
Gpt Delta

scholarly journals Novel Discoveries in Immune Dysregulation in Inborn Errors of Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Anwen Ren ◽  
Wei Yin ◽  
Heather Miller ◽  
Lisa S. Westerberg ◽  
Fabio Candotti ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Genome Sequencing ◽  
Immune Dysregulation ◽  
Genetic Mutation ◽  
Disease Monitoring ◽  
Whole Genome ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome

With the expansion of our knowledge on inborn errors of immunity (IEI), it gradually becomes clear that immune dysregulation plays an important part. In some cases, autoimmunity, hyperinflammation and lymphoproliferation are far more serious than infections. Thus, immune dysregulation has become significant in disease monitoring and treatment. In recent years, the wide application of whole-exome sequencing/whole-genome sequencing has tremendously promoted the discovery and further studies of new IEI. The number of discovered IEI is growing rapidly, followed by numerous studies of their pathogenesis and therapy. In this review, we focus on novel discovered primary immune dysregulation diseases, including deficiency of SLC7A7, CD122, DEF6, FERMT1, TGFB1, RIPK1, CD137, TET2 and SOCS1. We discuss their genetic mutation, symptoms and current therapeutic methods, and point out the gaps in this field.

scholarly journals Metastatic colorectal cancer and severe hypocalcemia following irinotecan administration in a patient with X-linked agammaglobulinemia: a case report

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Mingming Li ◽  
Wei Chen ◽  
Xiaomeng Sun ◽  
Zhipeng Wang ◽  
Xun Zou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Drug Monitoring ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Drug Monitoring ◽  
Treatment Cycle ◽  
Germline Mutations ◽  
Therapeutic Drug ◽  
Immune Disorder ◽  
Whole Exome

Abstract Background X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutations in the Bruton tyrosine kinase (BTK) gene on X chromosome. These mutations disturb B-cell development, decrease immunoglobulin levels, increase susceptibility to infection or neoplasms, and increase the risk of developing colorectal cancer (CRC). For occasional cases of CRC have been reported in XLA patients, low levels of B lymphocytes and immunoglobulins induced by congenital immune disorder make them more susceptible to drug-related toxicities (DRT). Therefore, gene sequencing, therapeutic drug monitoring and any possible measurement to predict DRT should be considered before determining the course of chemotherapy for XLA patients with CRC. Case presentation In this study, we reported a 21-year-old male who developed metastatic CRC in the context of XLA. Since the whole exome sequencing and therapeutic drug monitoring did not reveal any predictive markers of DRT, we applied standard first-line chemotherapy to the patient. However, progressive disease occurred after the fifth treatment cycle. Therefore, the administration of oxaliplatin was changed to irinotecan as second-line therapy. After that, the patient firstly suffered from severe hypocalcemia and eventually died due to metastatic CRC after the eighth treatment cycle. The overall survival time was 7.5 months. Conclusions This study reported the first written record of a Chinese XLA patient with metastatic CRC and severe hypocalcemia. Whole exome sequencing and bioinformatic analysis indicated the somatic mutations in ABCA6, C6 and PAX3 genes might contribute to the early-onset and metastasis CRC. Besides, a number of germline mutations in genes related to calcium metabolism (CACNA2D4, CD36, etc.) and the administration of irinotecan were speculated to be the causes of severe hypocalcemia. We therefore suggested that in order to avoid severe DRT, clinicians should take genetic background and therapeutic drug monitoring into consideration while planning chemotherapy treatment for XLA patients with CRC.

Identification of Two New DBA Genes, RPS27 and RPL27, by Whole-Exome Sequencing in Diamond-Blackfan Anemia Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 984-984 ◽  
Author(s):  
Etsuro Ito ◽  
Kenichi Yoshida ◽  
Yusuke Okuno ◽  
Aiko Sato-Otsubo ◽  
Tsutomu Toki ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Germline Mutations ◽  
Steroid Treatment ◽  
Single Amino Acid ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Diamond Blackfan Anemia ◽  
Whole Exome ◽  
Increased Risk

Abstract Abstract 984 Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome, characterized by red blood cell aplasia, macrocytic anemia, and increased risk of malignancy. Approximately 90% of patients present during the first year of life or in early childhood. About 40–50% of DBA cases are familial with autosomal dominant, while the remainder is sporadic cases whose mode of inheritance is largely unknown. Although anemia is the most prominent feature of DBA, up to 40% of patients also accompany other symptoms including growth retardation and/or a variety of congenital malformations. Recent studies have shown that the disease could be associated with heterozygous mutations in ribosomal protein (RP) genes, including six small subunit RP genes RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26 as well as four large subunit RP genes RPL5, RPL11, RPL26, and RPL35A, which collectively account for about 50% of patients with DBA. In addition, germline mutations in the GATA1 gene encoding a hematopoietic transcription factor, have been also reported in two DBA families. However, it is clear that the molecular etiology of many DBA cases remains to be covered. To identify new mutations that are responsible for DBA, we performed whole-exome sequencing on 40 DBA patients with no documented mutations/deletions involving known DBA genes. After excluding all variants registered in the 1000 Genomes Project, or dbSNP131, or found in our inhouse SNP database, we searched for non-synonymous mutations involving RP genes as possible candidate for novel DBA genes. In this study, we identified probable pathogenic mutations in two novel RP genes, RPS27 and RPL27 in two patients. The first case was a 1-year-old girl who harbored a single nucleotide substitution at the splice acceptor site in intron 1 of RPL27 (c.-2–1G>A), which results in splicing error. She had atrial septal defect and pulmonary stenosis, and responded to steroid treatment. The second case was a 2-year-old girl carrying a frameshift deletion of RPS27 (c.90delC, p.Tyr31ThrfsX5), leading to a premature truncation. This patient had no abnormalities and responded to steroid treatment. An additional five missense SNVs affecting single cases was identified in five genes, including RPL3L, RPL8, RPL13, RPL18A, and RPL31, together with two in-frame deletions of RPL6 and RPL14 in two patients, which cause deletion of a single amino-acid. However, the pathological significance in these 7 cases is uncertain. In the remaining 31 patients, no mutations were detected in RP genes. In conclusion, we identified novel germline mutations of RP genes that could be responsible for DBA, further confirming the concept that the RP genes are common targets of germline mutations in DBA patients and also suggested the presence of non-RP gene targets for DNA. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document