Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease

Gonorazky, Hernan; Naumenko, Sergey; Ramani, Arun; Nelakuditi, Viswateja; Mashouri, Pouria; Wang, Peiqui; Kao, Dennis; Ohri, Krish; Viththiyapaskaran, Senthuri; Tarnopolsky, Mark A.; Mathews, Katherine D.; Moore, Steven A.; Osorio, Andres Nascimiento; Villanova, David; Kemaladewi, Dwi U.; Cohn, Ronald D.; Brudno, Michael; Dowling, James J.

doi:10.1016/j.ajhg.2019.04.004

Cited by 144 publications

(104 citation statements)

References 79 publications

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“…RNA sequencing (RNAseq) is a convenient second tier test that complements a DNA-based method and is able to identify possible elusive variants [127,128]. The low detection rate of DNA tests is probably due to several reasons.…”

Section: Rna Sequencing As Second Tier Testmentioning

confidence: 99%

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

Savarese

Välipakka

Johari

et al. 2020

JND

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Human genes have a variable length. Those having a coding sequence of extraordinary length and a high number of exons were almost impossible to sequence using the traditional Sanger-based gene-by-gene approach. High-throughput sequencing has partly overcome the size-related technical issues, enabling a straightforward, rapid and relatively inexpensive analysis of large genes. Several large genes (e.g. TTN, NEB, RYR1, DMD) are recognized as disease-causing in patients with skeletal muscle diseases. However, because of their sheer size, the clinical interpretation of variants in these genes is probably the most challenging aspect of the high-throughput genetic investigation in the field of skeletal muscle diseases. The main aim of this review is to discuss the technical and interpretative issues related to the diagnostic investigation of large genes and to reflect upon the current state of the art and the future advancements in the field.

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Section: Rna Sequencing As Second Tier Testmentioning

confidence: 99%

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

Savarese

Välipakka

Johari

et al. 2020

JND

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“…MAE, or “allelic expression imbalance,” whereby one allele is silenced leaving only the other allele expressed, plays an important role in reprioritizing heterozygous rare SNVs called by WES and WGS . In the genomic analysis pipeline, these variants are filtered out due to the lack of a partner variant in biallelic autosomal recessive inheritance .…”

Section: Transcriptomicsmentioning

confidence: 99%

“…Furthermore, the top candidate tissue for testing—the primary affected tissue—is frequently inaccessible for sampling, necessitating choice of a surrogate tissue. Selection of the optimal tissue for study can be guided by gene expression databases, such as GTEx comprising approximately 11 500 RNA‐seq samples across more than 50 tissue sites (https://gtexportal.org/home/) and the recently developed web‐based tool Panel Analysis of Gene Expression (PAGE) …”

Section: Transcriptomicsmentioning

confidence: 99%

The diagnosis of inborn errors of metabolism by an integrative “multi‐omics” approach: A perspective encompassing genomics, transcriptomics, and proteomics

Stenton

Kremer

Kopajtich

et al. 2019

J of Inher Metab Disea

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Given the rapidly decreasing cost and increasing speed and accessibility of massively parallel technologies, the integration of comprehensive genomic, transcriptomic, and proteomic data into a “multi‐omics” diagnostic pipeline is within reach. Even though genomic analysis has the capability to reveal all possible perturbations in our genetic code, analysis typically reaches a diagnosis in just 35% of cases, with a diagnostic gap arising due to limitations in prioritization and interpretation of detected variants. Here we review the utility of complementing genetic data with transcriptomic data and give a perspective for the introduction of proteomics into the diagnostic pipeline. Together these methodologies enable comprehensive capture of the functional consequence of variants, unobtainable by the analysis of each methodology in isolation. This facilitates functional annotation and reprioritization of candidate genes and variants—a promising approach to shed light on the underlying molecular cause of a patient's disease, increasing diagnostic rate, and allowing actionability in clinical practice.

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“…Verlässliche Vorhersagen sind jedoch bioinformatisch kaum möglich, wenn exonische Splice-Enhancer-Motive betroffen sind. In der Aufdeckung solcher Mutationen liegt ein großes Potential der RNA-Sequenzierung [38][39][40]. Die systematische Anwendung von Transkriptom-Analysen für seltene Erkrankungen wird im Artikel von Prokisch behandelt.…”

Section: Splicemutationen In Der Kodierendenunclassified

NGS: Gestern, heute und morgen

Bolz

Hoischen

2019

Medizinische Genetik

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Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease

Cited by 144 publications

References 79 publications

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

The diagnosis of inborn errors of metabolism by an integrative “multi‐omics” approach: A perspective encompassing genomics, transcriptomics, and proteomics

NGS: Gestern, heute und morgen

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