International CRDS Registry

Официальное название

International Calcium Release Deficiency Syndrome Registry

Обзор

Calcium Release Deficiency Syndrome (CRDS) is a newly discovered genetic arrhythmia syndrome that confers a risk of life-threatening arrhythmias secondary to RYR2 loss-of-function. The International CRDS registry has been designed to facilitate large-scale evaluation of CRDS, including its phenotypic spectrum, approaches to risk stratification, and optimal treatment strategies.

Подробное описание

Calcium Release Deficiency Syndrome (CRDS) is a recently discovered inherited arrhythmia syndrome that predisposes to malignant ventricular arrhythmias and sudden cardiac death (SCD). The underlying genetic culprit of CRDS is RYR2, which encodes the cardiac ryanodine receptor. In contrast to Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), which stems from pathogenic RYR2 gain-of-function, CRDS manifests secondary to RyR2 loss-of-function. Enrolment into the CRDS registry requires that the putative disease causing RYR2 variant is confirmed to result in a loss-of-function on in vitro functional analysis. Individuals possessing an RYR2 truncating variant or large copy number variant will be eligible for enrolment into a second registry arm. Patients with a suspected CRDS diagnosis whose RYR2 variant is found not to impact function will be entered into a control arm of the registry.

Given its recent discovery, our understanding of CRDS remains in its infancy. The International CRDS registry has been designed to facilitate evaluation of large numbers of CRDS patients and enable robust insights to hopefully improve management of affected patients and families.

Первичные конечные точки

• Malignant Ventricular Arrhythmia [Срок оценки: 5 years]

Критерии участия

CRDS Cohort

Inclusion Criterion:

\- Presence of a rare\* RYR2 variant that is characterized to be loss-of-function based on in vitro testing#

RYR2 Truncating and Large CNV Cohort

Inclusion Criterion:

\- Presence of a rare\* RYR2 truncating variant and/or large copy number variant involving the RYR2 gene.

Carriers of a Non-Functional RYR2 variant

Inclusion Criterion:

\- Presence of a rare\* RYR2 variant that is characterized to be neither loss- nor gain-of-function based on in vitro testing#

\*rare defined as gnomAD prevalence < 0.1%

#RYR2 in vitro functional testing will be performed in the laboratory of Dr. Wayne Chen (University of Calgary)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Канада · 8 центров

• University of Calgary — Calgary
• Children's & Women's Health Centre of British Columbia — Vancouver
• The University of British Columbia — Vancouver
• Hamilton General Hospital — Hamilton
• London Health Sciences Centre - University Hospital — London
• Ottawa Heart Institute — Ottawa
• Montréal Heart Institute — Montreal
• Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval — Québec

США · 4 центра

• University of California — San Francisco
• Mayo Clinic — Rochester
• Duke University — Durham
• Inova Health Care Services — Fairfax

Бельгия · 2 центра

• Antwerp University Hospital — Edegem
• Universitair Ziekenhuis Brussel — Brussels

Великобритания · 2 центра

• Oxford University Hospitals — Oxford
• City St George's, University of London — London

Австралия · 1 центр

• Garvan Institute of Medical Research — Darlinghurst

Дания · 1 центр

• Aarhus University Hospital — Aarhus

Франция · 1 центр

• CHU de Bordeaux — Bordeaux

Израиль · 1 центр

• Shaare Zedek Medical Center — Jerusalem

Публикации

• Sun B, Yao J, Ni M, Wei J, Zhong X, Guo W, Zhang L, Wang R, Belke D, Chen YX, Lieve KVV, Broendberg AK, Roston TM, Blankoff I, Kammeraad JA, von Alvensleben JC, Lazarte J, Vallmitjana A, Bohne LJ, Rose RA, Benitez R, Hove-Madsen L, Napolitano C, Hegele RA, Fill M, Sanatani S, Wilde AAM, Roberts JD, Priori SG, Jensen HK, Chen SRW. Cardiac ryanodine receptor calcium release deficiency syndrome. Sci PMID 33536282
• Roston TM, Wei J, Guo W, Li Y, Zhong X, Wang R, Estillore JP, Peltenburg PJ, Noguer FRI, Till J, Eckhardt LL, Orland KM, Hamilton R, LaPage MJ, Krahn AD, Tadros R, Vinocur JM, Kallas D, Franciosi S, Roberts JD, Wilde AAM, Jensen HK, Sanatani S, Chen SRW. Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome. JAMA Cardiol. 2022 J PMID 34730774
• Li Y, Wei J, Guo W, Sun B, Estillore JP, Wang R, Yoruk A, Roston TM, Sanatani S, Wilde AAM, Gollob MH, Roberts JD, Tseng ZH, Jensen HK, Chen SRW. Human RyR2 (Ryanodine Receptor 2) Loss-of-Function Mutations: Clinical Phenotypes and In Vitro Characterization. Circ Arrhythm Electrophysiol. 2021 Sep;14(9):e010013. doi: 10.1161/CIRCEP.121.010013. Epub 2021 Sep 1. PMID 34546788
• Ormerod JOM, Ormondroyd E, Li Y, Taylor J, Wei J, Guo W, Wang R, Sarton CNS, McGuire K, Dreau HMP, Taylor JC, Ginks MR, Rajappan K, Chen SRW, Watkins H. Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome. Circ Genom Precis Med. 2022 Feb;15(1):e003589. doi: 10.1161/CIRCGEN.121.003589. Epub 2021 Dec 24. PMID 34949103
• Ni M, Li Y, Wei J, Song Z, Wang H, Yao J, Chen YX, Belke D, Estillore JP, Wang R, Vallmitjana A, Benitez R, Hove-Madsen L, Feng W, Chen J, Roston TM, Sanatani S, Lehman A, Chen SRW. Increased Ca2+ Transient Underlies RyR2-Related Left Ventricular Noncompaction. Circ Res. 2023 Jul 7;133(2):177-192. doi: 10.1161/CIRCRESAHA.123.322504. Epub 2023 Jun 16. PMID 37325910
• Ni M, Dadon Z, Ormerod JOM, Saenen J, Hoeksema WF, Antiperovitch P, Tadros R, Christiansen MK, Steinberg C, Arnaud M, Tian S, Sun B, Estillore JP, Wang R, Khan HR, Roston TM, Mazzanti A, Giudicessi JR, Siontis KC, Alak A, Acosta JG, Divakara Menon SM, Tan NS, van der Werf C, Nazer B, Vivekanantham H, Pandya T, Cunningham J, Gula LJ, Wong JA, Amit G, Scheinman MM, Krahn AD, Ackerman MJ, Priori SG, PMID 38900490

Идентификаторы

NCT: NCT06508164 · 16861

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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