Transcript-Specific Loss-of-Function Variants in


Journal

Neurology. Genetics
ISSN: 2376-7839
Titre abrégé: Neurol Genet
Pays: United States
ID NLM: 101671068

Informations de publication

Date de publication:
Feb 2022
Historique:
received: 07 05 2021
accepted: 08 10 2021
entrez: 13 12 2021
pubmed: 14 12 2021
medline: 14 12 2021
Statut: epublish

Résumé

Our objective was to improve rare variant interpretation using statistical measures as well as publicly accessible annotation of expression levels and tissue specificity of different splice isoforms. We describe rare In-house exome and genome data sets (n = 11,539) were screened for rare heterozygous missense and putative loss-of-function (pLoF) variants in Six different heterozygous pLoFs in Our data provide strong evidence for

Sections du résumé

BACKGROUND AND OBJECTIVES OBJECTIVE
Our objective was to improve rare variant interpretation using statistical measures as well as publicly accessible annotation of expression levels and tissue specificity of different splice isoforms. We describe rare
METHODS METHODS
In-house exome and genome data sets (n = 11,539) were screened for rare heterozygous missense and putative loss-of-function (pLoF) variants in
RESULTS RESULTS
Six different heterozygous pLoFs in
DISCUSSION CONCLUSIONS
Our data provide strong evidence for

Identifiants

pubmed: 34901436
doi: 10.1212/NXG.0000000000000644
pii: NG2021017063
pmc: PMC8656243
doi:

Types de publication

Journal Article

Langues

eng

Pagination

e644

Informations de copyright

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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Auteurs

Joohyun Park (J)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Annemarie Reilaender (A)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Jan N Petry-Schmelzer (JN)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Petra Stöbe (P)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Isabell Cordts (I)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Florian Harmuth (F)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Maren Rautenberg (M)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Sarah E Woerz (SE)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

German Demidov (G)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Marc Sturm (M)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Stephan Ossowski (S)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Eva M C Schwaibold (EMC)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Gilbert Wunderlich (G)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Sebastian Paus (S)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Carsten Saft (C)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Tobias B Haack (TB)

Institute of Medical Genetics and Applied Genomics (J.P., P.S., F.H., M.R., S.E.W., G.D., M.S., S.O.), University of Tübingen, Tübingen. Germany; Department of Neurology University Hospital (A.R.), Goethe University Frankfurt, Frankfurt. Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology (J.N.P-S., G.W.), Cologne. Germany; Department of Neurology (I.C.,), Klinikum rechts der Isar, Technical University Munich, Munich. Germany; Institute of Human Genetics (E.M.C.S.), Heidelberg University, Heidelberg. Germany; University of Cologne (G.W.), Faculty of Medicine and University Hospital Cologne, Centre for Rare Diseases, Cologne, Germany; Department of Neurology (S.P.), GFO Clinics Troisdorf, Troisdorf. Germany; Department of Neurology (C.S.), Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum. Germany; Centre for Rare Diseases, University of Tübingen (T.B.H.), Tübingen. Germany.

Classifications MeSH