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Cited by 590Genomics and Rare DiseasesMitochondrial Function and PathologyMetabolism and Genetic Disorders

Genetic diagnosis of Mendelian disorders via RNA sequencing

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Kremer, Laura S., Bader, Daniel M., Mertes, Christian, Kopajtich, Robert, Pichler, Garwin, Iuso, Arcangela, Haack, Tobias B., Graf, Elisabeth +24 more·2017·Nature Communications
DOI 10.1038/ncomms15824PMC PMC5499207

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Abstract

Across a variety of Mendelian disorders, ∼50–75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private exons often arise from cryptic splice sites providing an important clue for variant prioritization. One such event is found in the complex I assembly factor TIMMDC1 establishing a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants and provides examples of intronic loss-of-function variants with pathological relevance.

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  • Approximately 50-75% of patients with Mendelian disorders do not receive a genetic diagnosis based on WES that could identify disease-causing variants in noncoding regions.

    “Approximately 50–75% of patients with Mendelian disorders do not receive a genetic diagnosis based on WES that could identify disease-causing variants in noncoding regions [41,42].”

    From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [42]

  • Previous studies have reported that RNA-Seq helps interpret VUSs identified through WES/WGS when linked to an aberrant transcript event, and detects variants missed by current standard diagnostic approaches in rare diseases.

    “Previous studies have reported that RNA-Seq helps interpret VUSs identified through WES/WGS when linked to an aberrant transcript event, and detects variants missed by current standard diagnostic approaches in rare diseases [42,45,46].”

    From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [42]

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Authors
Kremer, L. S., Bader, D. M., Mertes, C., Kopajtich, R., Pichler, G., Iuso, A., Haack, T. B., Graf, E., Schwarzmayr, T., Terrile, C., Koňaříková, E., Repp, B., Kastenmüller, G., Adamski, J., Lichtner, P., Leonhardt, C., Funalot, B., Donati, A., Tiranti, V., Lombes, A., Jardel, C., Gläser, D., Taylor, R. W., Ghezzi, D., Mayr, J. A., Rötig, A., Freisinger, P., Distelmaier, F., Strom, T. M., Meitinger, T., Gagneur, J., & Prokisch, H.
Affiliations
  • TUM Klinikum (DE)
  • Technical University of Munich (DE)
  • Max Planck Institute of Biochemistry (DE)
  • Helmholtz Munich (DE)
  • Meyer Children's Hospital (IT)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • Inserm (FR)
  • Genetikum (DE)
  • Wellcome Centre for Mitochondrial Research (GB)
  • Paracelsus Medical University (AT)
  • Kreiskliniken Reutlingen (DE)
  • Heinrich Heine University Düsseldorf (DE)
Corresponding author
  • Gagneur, Julien
  • Prokisch, Holger
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-06-12
Volume
8
Issue
1
Pages
15824-15824
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms15824
PMC
PMC5499207
OpenAlex
W2950545834
Cited by
590
References
9
Citations by year
2026: 41 · 2025: 49 · 2024: 61 · 2023: 56 · 2022: 86 · 2021: 80 · 2020: 83 · 2019: 66 · 2018: 47 · 2017: 18 · 2013: 1 · 2012: 1
FWCI
38.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Site cant be reached (submittedVersion, cc-by)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • Wellcome Trust
  • Deutsches Zentrum für Herz-Kreislaufforschung
  • E-Rare (FWF I 920-B13, 01GM1207)
  • European Commission (317433)
  • Deutsche Forschungsgemeinschaft (EXC 1010, 01GM1207)
  • Bundesministerium für Bildung und Forschung (FKZ01ZX1405C, 01GM1207, 01ZX1405C, 01GM1603, FKZ 01ZX1405A)
  • Austrian Science Fund (I920, J41J11000420001)
  • Fondazione Pierfranco e Luisa Mariani
  • Medical Research Council (203105/Z/16/Z, G0601943, EU FP7)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
monogenic disorders, mitochondrial disease, transcriptome sequencing, non-coding variants, aberrant splicing, cryptic splice site, monoallelic expression, rare variants, variant prioritization, complex I assembly, fibroblasts, molecular diagnosis
MeSH terms
Humans, RNA Splicing, Sequence Analysis, RNA, Diagnostic Techniques and Procedures, Gene Expression Profiling, Mitochondrial Diseases

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