RNA sequencing reveals the consequences of a novel insertion in dedicator of cytokinesis-8

Khan, Shaheen; Kuruvilla, Merin; Hagin, David; Wakeland, Benjamin; Liang, Chao; Vishwanathan, Kasthuribhai; Gatti, Richard A.; Torgersen, Troy R.; Abraham, Roshini S.; Wakeland, Edward K.; Oers, Nicolai S. C. van; Morena, M. Teresa de la

doi:10.1016/j.jaci.2015.11.033

Cited by 6 publications

(4 citation statements)

References 15 publications

(9 reference statements)

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“…LOF mutations in STAT3 cause AD hyper-IgE syndrome whereas GOF mutations, sometimes at the same position, lead to lymphoproliferation and auto-immunity (63–66). Mutations in DOCK8 typically result in AR combined immunodeficiency (CID), with severe eczema and elevated serum IgE levels, but they can also produce a CID phenotype without eczema or hyper-IgE (67, 68). Perhaps the most beautiful example of phenotypic diversity is that provided by RAG1 and RAG2 mutations, ranging from severe combined immunodeficiency to CID with autoimmunity.…”

Section: Discoveries Of Pid-causing Mutations By Ngsmentioning

confidence: 99%

Exome and genome sequencing for inborn errors of immunity

Meyts

Bosch

Bolze

et al. 2016

Journal of Allergy and Clinical Immunology

167

148

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The advent of next generation sequencing (NGS) in 2010 has transformed medicine and particularly the growing field of monogenic inborn errors of immunity, including primary immunodeficiencies (PID). NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with PID. Whole-exome sequencing (WES) is presently the most cost-effective approach for PID research and diagnostics, though whole genome sequencing (WGS) offers several advantages. The scientific or diagnostic challenge consists in selecting one or two candidate variants among thousands of NGS calls. Variant- and gene-level computational methods as well as immunological hypotheses can help to narrow down this genome-wide search. The key to success is a well-informed genetic hypothesis on three key aspects: mode of inheritance, clinical penetrance, and genetic heterogeneity of the condition. This determines the search strategy and the frequency cut-offs for candidate alleles. Subsequent functional validation of the disease-causing effect of the candidate variant is critical. Even the most up-to-date dry lab cannot clinch this validation without a seasoned wet lab. The multifariousness of variations entails an experimental rigor even greater than traditional Sanger sequencing-based approaches, in order not to assign PID to false positives. Finding the needle in the haystack takes patience, prudence, and discernment.

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Section: Discoveries Of Pid-causing Mutations By Ngsmentioning

confidence: 99%

Exome and genome sequencing for inborn errors of immunity

Meyts

Bosch

Bolze

et al. 2016

Journal of Allergy and Clinical Immunology

167

148

View full text Add to dashboard Cite

show abstract

“…The transcriptomic landscape provides an excellent opportunity for advancement of diagnostic yield, and transcriptional profiling is already being utilized across a range of disorders to help build a "molecular fingerprint" of disease and better inform variantfiltering processes. The immunology community has made a case for PID diagnosis to be supported using transcriptional profiling using whole-transcriptome sequencing (Moens et al, 2014), and these are being answered with examples in primary immunodeficiency cases such as Dock8 CID, GATA2 deficiency, and X-linked reticulate pigmentary disorder (XLPDR) (Hsu et al, 2013;Khan et al, 2016;Starokadomskyy et al, 2016). Over the coming years, an extended diagnostic approach to PID testing may develop that builds on a clinical module of phenotype, family history, and baseline immunological testing.…”

Section: Discussionmentioning

confidence: 99%

Exploring the RNA Gap for Improving Diagnostic Yield in Primary Immunodeficiencies

2019

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Challenges in diagnosing primary immunodeficiency are numerous and diverse, with current whole-exome and whole-genome sequencing approaches only able to reach a molecular diagnosis in 25-60% of cases. We assess these problems and discuss how RNA-focused analysis has expanded and improved in recent years and may now be utilized to gain an unparalleled insight into cellular immunology. We review how investigation into RNA biology can give information regarding the differential expression, monoallelic expression, and alternative splicing-which have important roles in immune regulation and function. We show how this information can inform bioinformatic analysis pipelines and aid in the variant filtering process, expediting the identification of causal variants-especially those affecting splicing-and enhance overall diagnostic ability. We also demonstrate the challenges, which remain in the design of this type of investigation, regarding technological limitation and biological considerations and suggest potential directions for the clinical applications.

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“…Northern blot analysis for miRNAs was performed as previously described (Belkaya et al, 2011). Gene expression was performed as described (Khan et al, 2016). For gene expression comparisons, the Affymetrix Clariom S TM mouse array was used, which focuses on 20,000 well annotated genes (Thermo-Fisher Scientific).…”

Section: Star+methods Key Resources Tablementioning

confidence: 99%

MIR205HG Is a Long Noncoding RNA that Regulates Growth Hormone and Prolactin Production in the Anterior Pituitary

Hoover

Dozmorov

et al. 2019

Developmental Cell

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MicroRNAs (miRNAs) are processed from primary miRNA transcripts (pri-miRNAs), many of which are annotated as long noncoding RNAs (lncRNAs). We assessed whether MIR205HG, the host gene for miR-205, has independent functions as an lncRNA. Comparing mice with targeted deletions of MIR205HG and miR-205 revealed a functional role for the lncRNA in the anterior pituitary. Mice lacking MIR205HG had a temporal reduction in Pit1, growth hormone, and prolactin. This was mediated, in part, through the ability of this lncRNA to bind and regulate the transcriptional activity of Pit1 in conjunction with Zbtb20. Knockdown of MIR205HG in lactotropes decreased the expression of Pit1, Zbtb20, prolactin, and growth hormone, while its overexpression enhanced the levels of these transcripts. The effects of MIR205HG on the pituitary were independent of miR-205. The data support a role for MIR205HG as an lncRNA that regulates growth hormone and prolactin production in the anterior pituitary.

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RNA sequencing reveals the consequences of a novel insertion in dedicator of cytokinesis-8

Abstract: options from Sparo, all outside the submitted work. M. Cernadas reports grants from the NIH during the conduct of the study. J. M. Green has received a grant from the NIH. The rest of the authors declare that they have no relevant conflicts of interest.

Cited by 6 publications

References 15 publications

Exome and genome sequencing for inborn errors of immunity

Exome and genome sequencing for inborn errors of immunity

Exploring the RNA Gap for Improving Diagnostic Yield in Primary Immunodeficiencies

MIR205HG Is a Long Noncoding RNA that Regulates Growth Hormone and Prolactin Production in the Anterior Pituitary

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