Julian O M Ormerod1,2, Elizabeth Ormondroyd1, Yanhui Li3,4, John Taylor5, Jinhong Wei3, Wenting Guo3, Ruiwu Wang3, Caroline N S Sarton5, Karen McGuire5, Helene M P Dreau6, Jenny C Taylor7,5, Matthew R Ginks2, Kim Rajappan2, S R Wayne Chen3, Hugh Watkins1,7. 1. Division of Cardiovascular Medicine, Radcliffe Department of Medicine (J.O.M.O., E.O., H.W.), University of Oxford, United Kingdom. 2. Cardiac Rhythm Management Service, Oxford Heart Centre, John Radcliffe Hospital, United Kingdom (J.O.M.O., M.R.G., K.R.). 3. Department of Physiology and Pharmacology, The Libin Cardiovascular Institute, University of Calgary, AB, Canada (Y.L., J.W., W.G., R.W., S.R.W.C.). 4. Department of Internal Medicine, Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.L.). 5. Oxford Medical Genetics Laboratories, Cardiac Service, Oxford University Hospitals NHS Trust, The Churchill Hospital, United Kingdom (J.T., C.N.S.S., K.M., J.C.T.). 6. Molecular Diagnostic Centre, Department of Oncology (H.M.P.D.), University of Oxford, United Kingdom. 7. Oxford Biomedical Research Centre and Wellcome Centre for Human Genetics (J.C.T., H.W.), University of Oxford, United Kingdom.
Abstract
BACKGROUND: A novel familial arrhythmia syndrome, cardiac ryanodine receptor (RyR2) calcium release deficiency syndrome (CRDS), has recently been described. We evaluated a large and well characterized family to assess provocation testing, risk factor stratification and response to therapy in CRDS. METHODS: We present a family with multiple unheralded sudden cardiac deaths and aborted cardiac arrests, primarily in children and young adults, with no clear phenotype on standard clinical testing. RESULTS: Genetic analysis, including whole genome sequencing, firmly established that a missense mutation in RYR2, Ala4142Thr, was the underlying cause of disease in the family. Functional study of the variant in a cell model showed RyR2 loss-of-function, indicating that the family was affected by CRDS. EPS (Electrophysiological Study) was undertaken in 9 subjects known to carry the mutation, including a survivor of aborted sudden cardiac death, and the effects of flecainide alone and in combination with metoprolol were tested. There was a clear gradation in inducibility of nonsustained and sustained ventricular arrhythmia between subjects at EPS, with the survivor of aborted sudden cardiac death being the most inducible subject. Administration of flecainide substantially reduced arrhythmia inducibility in this subject and abolished arrhythmia in all others. Finally, the effects of additional metoprolol were tested; it increased inducibility in 4/9 subjects. CONCLUSIONS: The Ala4142Thr mutation of RYR2 causes the novel heritable arrhythmia syndrome CRDS, which is characterized by familial sudden death in the absence of prior symptoms or a recognizable phenotype on ambulatory monitoring or exercise stress testing. We increase the experience of a specific EPS protocol in human subjects and show that it is helpful in establishing the clinical status of gene carriers, with potential utility for risk stratification. Our data provide evidence that flecainide is protective in human subjects with CRDS, consistent with the effect previously shown in a mouse model.
BACKGROUND: A novel familial arrhythmia syndrome, cardiac ryanodine receptor (RyR2) calcium release deficiency syndrome (CRDS), has recently been described. We evaluated a large and well characterized family to assess provocation testing, risk factor stratification and response to therapy in CRDS. METHODS: We present a family with multiple unheralded sudden cardiac deaths and aborted cardiac arrests, primarily in children and young adults, with no clear phenotype on standard clinical testing. RESULTS: Genetic analysis, including whole genome sequencing, firmly established that a missense mutation in RYR2, Ala4142Thr, was the underlying cause of disease in the family. Functional study of the variant in a cell model showed RyR2 loss-of-function, indicating that the family was affected by CRDS. EPS (Electrophysiological Study) was undertaken in 9 subjects known to carry the mutation, including a survivor of aborted sudden cardiac death, and the effects of flecainide alone and in combination with metoprolol were tested. There was a clear gradation in inducibility of nonsustained and sustained ventricular arrhythmia between subjects at EPS, with the survivor of aborted sudden cardiac death being the most inducible subject. Administration of flecainide substantially reduced arrhythmia inducibility in this subject and abolished arrhythmia in all others. Finally, the effects of additional metoprolol were tested; it increased inducibility in 4/9 subjects. CONCLUSIONS: The Ala4142Thr mutation of RYR2 causes the novel heritable arrhythmia syndrome CRDS, which is characterized by familial sudden death in the absence of prior symptoms or a recognizable phenotype on ambulatory monitoring or exercise stress testing. We increase the experience of a specific EPS protocol in human subjects and show that it is helpful in establishing the clinical status of gene carriers, with potential utility for risk stratification. Our data provide evidence that flecainide is protective in human subjects with CRDS, consistent with the effect previously shown in a mouse model.
Entities:
Keywords:
arrhythmias; calcium; phenotype; ryanodine receptor; young adult
Authors: Norbert Szentandrássy; Zsuzsanna É Magyar; Judit Hevesi; Tamás Bányász; Péter P Nánási; János Almássy Journal: Int J Mol Sci Date: 2022-04-18 Impact factor: 6.208