Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders

Dekker, Jordy; Schot, Rachel; Bongaerts, Michiel; Valk, Walter G. de; Veghel-Plandsoen, Monique M. van; Monfils, Kathryn; Douben, Hannie; Elfferich, Peter; Kasteleijn, Esmee; Unen, Leontine van; Geeven, Geert; Saris, Jasper J.; Ierland, Yvette van; Verheijen, Frans W.; Sterre, Marianne L. T. van der; Niaraki, Farah Sadeghi; Smits, Daphne J.; Huidekoper, Hidde H.; Williams, Monique; Wilke, Martina; Verhoeven, Virginie Jm; Joosten, Marieke; Kievit, Anneke J.A.; Laar, Ingrid M.B.H. van de; Hoefsloot, Lies H.; Hoogeveen‐Westerveld, Marianne; Nellist, Mark; Mancini, Grazia M.S.; Ham, Tjakko J. van

doi:10.1016/j.ajhg.2022.12.015

Cited by 19 publications

(21 citation statements)

References 75 publications

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“…Frésard et al used this approach to systematically evaluate genetic, phenotypic and transcriptomic data. It is also possible to integrate multi‐omics data using the ACMG/AMP framework and guidelines for the clinical interpretation of RNA phenotypes have recently been proposed 27,37,40,88 . Kopajtich et al (2021) also integrated proteomics with genetic, phenotypic and RNA‐seq data and proposed a visualisation technique to facilitate clinical interpretation.…”

Section: Multi‐omics Integrationmentioning

confidence: 99%

“…It was successfully applied as a complementary approach to WES and WGS in more than 18 studies (Table S2). There are multiple case reports in which RNA‐sequencing (RNA‐seq) provided the necessary functional evidence to support a molecular diagnosis 24–39 . Transcriptomics can be used for VUS reclassification and for prioritisation of overlooked likely pathogenic variants.…”

Section: Transcriptomicsmentioning

confidence: 99%

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Integrative omics approaches to advance rare disease diagnostics

Smirnov

Konstantinovskiy

Prokisch

2023

J of Inher Metab Disea

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Over the past decade high‐throughput DNA sequencing approaches, namely whole exome and whole genome sequencing became a standard procedure in Mendelian disease diagnostics. Implementation of these technologies greatly facilitated diagnostics and shifted the analysis paradigm from variant identification to prioritisation and evaluation. The diagnostic rates vary widely depending on the cohort size, heterogeneity, and disease and range from around 30% to 50% leaving the majority of patients undiagnosed. Advances in omics technologies and computational analysis provide an opportunity to increase these unfavourable rates by providing evidence for disease‐causing variant validation and prioritisation. This review aims to provide an overview of the current application of several omics technologies including RNA‐sequencing, proteomics, metabolomics and DNA‐methylation profiling for diagnostics of rare genetic diseases in general and inborn errors of metabolism in particular.This article is protected by copyright. All rights reserved.

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Section: Multi‐omics Integrationmentioning

confidence: 99%

Section: Transcriptomicsmentioning

confidence: 99%

Integrative omics approaches to advance rare disease diagnostics

Smirnov

Konstantinovskiy

Prokisch

2023

J of Inher Metab Disea

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“…Since its first clinical application in 2017, 56,57 a variety of studies have applied RNA-seq to help diagnosing genetically unsolved patients with a variety of phenotypes, ranging from metabolic disorders to neurodevelopmental disorders presenting with epilepsies, yielding in most instances a diagnostic yield of up to 15%. [58][59][60][61][62][63][64] At some centers, clinical RNA-seq can now be diagnostically requested even in routine clinical care. 64 Benefits of RNA-seq include detection of gene expression changes thereby pinpointing to disease relevant genes and variants, as well as offering improved functional interpretation of deep-intronic variants affecting mRNA splicing.…”

Section: Transcriptomicsmentioning

confidence: 99%

“…[58][59][60][61][62][63][64] At some centers, clinical RNA-seq can now be diagnostically requested even in routine clinical care. 64 Benefits of RNA-seq include detection of gene expression changes thereby pinpointing to disease relevant genes and variants, as well as offering improved functional interpretation of deep-intronic variants affecting mRNA splicing. These types of variants are either not identified (ES) or are often classified as variants of unknown significance due to the lack of good in silico prediction models for the effects of such variants.…”

Section: Transcriptomicsmentioning

confidence: 99%

Solving the unsolved genetic epilepsies: Current and future perspectives

Johannesen,

Tümer,

Weckhuysen

et al. 2023

Epilepsia

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Many patients suffering from epilepsy undergo exome or genome sequencing as part of a diagnostic work‐up, however, many remain genetically unsolved. There are various factors that account for negative results in exome/genome sequencing for epilepsy patients; 1) the underlying cause is not genetic, 2) there is a complex polygenic explanation, 3) the illness is monogenic but the causative gene remains to be linked to a human disorder, 4) family segregation with reduced penetrance, 5) somatic mosaicism or the complexity of eg. a structural rearrangement, or 6) limited knowledge or diagnostic tools hinder the proper classification of a variant, resulting in its designation as a variant of unknown significance.The objective of this review is to outline some of the diagnostic options that lie beyond the exome/genome, and that might become clinically relevant within the foreseeable future. These options include: 1) re‐analysis of older exome/genome data as knowledge increases or symptoms change, 2) looking for somatic mosaicism or long‐read sequencing to detect low‐complexity repeat variants or specific structural variants missed by traditional exome/genome sequencing, 3) exploration of the non‐coding genome including disruption of topologically associated domains, long range non‐coding RNA or other regulatory elements, and finally 4) transcriptomics, DNA methylation signatures and metabolomics as complementary diagnostic methods that may be used in the assessment of variants of unknown significance. Some of these tools are currently not integrated into standard diagnostic work‐up. However, it is reasonable to expect that they will become increasingly available and improve current diagnostic capabilities, thereby enabling precision diagnosis in patients that are currently undiagnosed.

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“…Inmiddels kan in het Erasmus MC RNA-seq routinematig diagnostisch worden aangevraagd, bij voorkeur op afgenomen huidbiopten. Dit heeft al een groot aantal diagnoses opgeleverd voor een breed spectrum aan neuronale ontwikkelingsstoornissen, al dan niet gepaard gaand met epilepsie (Dekker et al, 2023). Een inmiddels eveneens veel gebruikte techniek is onderzoek van DNA methylatie (door middel van Episign) waarbij naar epigenetische veranderingen in het DNA wordt gezocht die correleren met bepaalde aandoeningen (Sadikovic et al, 2021), waaronder ook een aantal syndromen die gepaard gaan met epilepsie zoals het SETD1B-syndroom (Weerts et al, 2021) en het CHD2-syndroom.…”

Section: Nieuwe Diagnostische Technologieënunclassified

Het belang van het vinden van nieuwe genetische oorzaken van epilepsie

Barakat

2023

Epilepsie

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Ondanks grote technologische vooruitgang blijft vaak de helft van de patiënten met ernstige epilepsie op de kinderleeftijd zonder een genetische diagnose. In deze bijdrage sta ik stil bij het belang van een multidisciplinaire benadering voor deze patiëntengroep en bij nieuwe genetische technologieën en analysemethoden, om alsnog een diagnose te kunnen stellen, die uiteindelijk de weg kunnen openen naar precision medicine.

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Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders

Cited by 19 publications

References 75 publications

Integrative omics approaches to advance rare disease diagnostics

Integrative omics approaches to advance rare disease diagnostics

Solving the unsolved genetic epilepsies: Current and future perspectives

Het belang van het vinden van nieuwe genetische oorzaken van epilepsie

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