HNRNPA1 de novo Variant Associated with Early Childhood Onset, Rapidly Progressive Generalized Myopathy

Author:

Roos Andreas123,Häusler Martin4,Kollipara Laxmikanth5,Topf Ana6,Preusse Corinna7,Stucka Rolf8,Nolte Kay9,Strom Tim10,Berutti Riccardo1011,Jiang Xuehui12,Koll Randi7,Lochmüller Hanns31314,Schacht Sabine Maria15,Zahedi René P.512161718,Weis Joachim9,Senderek Jan8

Affiliation:

1. Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Duisburg–Essen, Essen, Germany

2. Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

3. Department of Medicine, Division of Neurology, Children’ s Hospital of Eastern Ontario Research Institute, The Ottawa Hospital, and Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada

4. Department of Paediatrics, Division of Neuropediatrics and Social Pediatrics, RWTH Aachen University Hospital, Aachen, Germany

5. Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V. Dortmund, Germany

6. John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK

7. Department of Neuropathology, Humboldt-Universität zu Berlin and Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany

8. Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilians University Munich, Munich, Germany

9. Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany

10. Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

11. Institute of Neurogenomics, Computational Health Centre, Helmholtz Zentrum München, Neuherberg, Germany

12. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada

13. Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain

14. Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center – University of Freiburg, Freiburg, Germany

15. Department of Diagnostic and Interventional Radiology, University Hospital RWTH, Aachen, Germany

16. Department of Internal Medicine, University of Manitoba, Winnipeg, Canada

17. Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, Canada

18. Cancer Care Manitoba Research Institute, Winnipeg, Canada

Abstract

HNRNPA1 variants are known to cause degenerative motoneuron and muscle diseases which manifests in middle age or later. We report on a girl with early childhood onset, rapidly progressive generalized myopathy including ultrastructural findings in line with a proteinopathy. Proteomics of patient-derived muscle and combined screening of genomic data for copy number variations identified a HNRNPA1 de novo intragenic deletion as causative for the phenotype. Our report expands the spectrum of HNRNPA1-related diseases towards early-childhood onset and adds HNRNPA1 to the growing list of ALS and myopathy genes for which certain mutations may cause severe pediatric phenotypes.

Publisher

IOS Press

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