Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice.

Chair of Experimental Genetics School of Life Science Weihenstephan Technische 83 Universität München Alte Akademie 8 85354 Freising Germany

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Laboratory Medicine and Pathobiology Faculty of Medicine University of Toronto Toronto ON Canada

Department of Life Science College of Natural Sciences Hanyang Institute of Bioscience and Biotechnology Research Institute for Natural Sciences Hanyang University Seoul 04763 Republic of Korea

European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Trust Genome Campus Hinxton Cambridgeshire CB10 1SD UK

Experimental Animal Division RIKEN BioResource Research Center 3 1 1 Koyadai Tsukuba Ibaraki 305 0074 Japan

German Center for Diabetes Research Ingolstädter Landstrasse 1 85764 Neuherberg Germany

Institute of Experimental Genetics and German Mouse Clinic Helmholtz Center Munich German Research Center for Environmental Health Ingolstädter Landstraße 1 85764 Neuherberg Germany

Integrated Bioresource Information Division RIKEN BioResource Research Center 3 1 1 Koyadai Tsukuba Ibaraki 305 0074 Japan

Integrative Physiology Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA

Korea Mouse Phenotyping Center Korea Research Institute of Bioscience and Biotechnology Daejeon Republic of Korea

Laboratory of Developmental Biology and Genomics College of Veterinary Medicine and Interdisciplinary Program for Bioinformatics Korea Mouse Phenotyping CenterBK21 Plus Program for Advanced Veterinary Science Research Institute for Veterinary ScienceSeoul National University 599 Gwanak Ro Gwanak Gu Seoul 08826 Republic of Korea

Molecular and Human Genetics Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA

Mouse Biology Program University of California 2795 2nd Street Suite 400 Davis CA 95618 USA

Technology and Development Team for Mouse Phenotype Analysis RIKEN BioResource Research Center 3 1 1 Koyadai Tsukuba Ibaraki 305 0074 Japan

The Centre for Phenogenomics Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital Toronto ON M5T 3H7 Canada

The Centre for Phenogenomics The Hospital for Sick Children Toronto ON M5T 3H7 Canada

The Jackson Laboratory 600 Main Street Bar Harbor ME 04609 USA

The Mary Lyon Centre MRC Harwell Harwell Campus Oxfordshire OX11 0RD UK

Université de Strasbourg CNRS INSERM Institut de La Clinique de La Souris PHENOMIN 1 Rue Laurent Fries 67404 Illkirch France

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