Eu opace (2025) 27, eua 189
h ps://doi.o g/10.1093/eu opace/eua 189
RAPID COMMUNICATION
No el ou -exon dele ion in yanodine
ecep o gene (RYR2) associa ed wi h mixed
elec ic and s uc u al ca diac pheno ype
Te eza S ibna
1
, Pe a Peldo a
1
, Ta iana Vosecka
1
, Tomas Roubicek
2,3
,
Milos Kubanek
4
, Robe Cihak
4
, Pe Peichl
4
, Jose Kau zne
4
,
Milan Macek J
1
, and Alice K ebso a
4
*
1
Depa men o Biology and Medical Gene ics, Second Facul y o Medicine, Cha les Uni e si y and Mo ol Uni e si y Hospi al, P ague, Czech Republic;
2
Depa men o Ca diology, Hospi al
Libe ec, Libe ec, Czech Republic;
3
Facul y o Heal h S udies, Technical Uni e si y Libe ec, Libe ec, Czech Republic; and
4
Depa men o Ca diology, Cen e o Inhe i ed Ca dio ascula
Diseases, IKEM, P ague, Czech Republic
Recei ed 22 June 2025; accep ed a e e ision 12 Augus 2025; online publish-ahead-o -p in 26 Augus 2025
Keywo ds RYR2 dele ion • CNV analysis • LV hype abecula iza ion • PVC om ao ic oo • Radio equency abla ion • E3DS
* Co esponding au ho . E-mail add ess: [email p o ec ed]
© The Au ho (s) 2025. Published by Ox o d Uni e si y P ess on behal o he Eu opean Socie y o Ca diology.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h ps://c ea i ecommons.o g/licenses/by/4.0/), which pe mi s un es ic ed euse,
dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
In oduc ion
Ryanodine ecep o 2 gene codes o a Ca
2+
channel in ol ed in exci-
a ion–con ac ion coupling in he ca diac muscle.
1,2
Missense mu a-
ions in RYR2 cause ca echolamine gic polymo phic en icula
achyca dia (CPVT),
3,4
while an exon 3 dele ion has been epo ed in
pa ien s wi h a iable clinical mani es a ions including sup a en icula
a hy hmias, conduc ion diso de s, en icula a hy hmias and le
en icula (LV) hype abecula iza ion.
5–9
This synd ome, also called
exon 3 dele ion synd ome (E3DS), is now conside ed a dis inc diag-
nos ic en i y among RYR2- yanodinopa hies.
10
He e, we epo a unique case o a ou -exon dele ion (3, 4, 5, and 6)
in he RYR2 gene in a Czech amily o h ee a ec ed indi iduals wi h
mixed elec ic and s uc u al ca diac pheno ype (Figu e 1).
P oband mani es ed wi h exe ion- ela ed syncope a he age o 45
yea s. Spon aneously e mina ing a ial ib illa ion (AF) and la e docu-
men ed sus ained en icula achyca dia oge he wi h LV hype abe-
cula iza ion wi h ansi o y educ ion o le en icula ejec ion
ac ion (LVEF 30%) and no la e gadolinium enhancemen (LGE) led
o ICD implan a ion in seconda y p e en ion sho ly a e ini ial diagno-
sis. Pulmona y ein isola ion was pe o med eaching no documen ed
AF e en du ing he 6-yea ollow-up. Adequa e ICD he apy o en-
icula ib illa ion (VF) esul ing om sinus hy hm du ing dancing a
he ball was obse ed (Figu e 1). On es and exe cise elec oca dio-
g ams (ECGs), equen p ema u e en icula con ac ions (PVCs)
om he le ao ic cusp as well as bidi ec ional PVCs upon exe ion
we e documen ed (Figu e 1).
Family cascade sc eening led o he iden i ica ion o LV hype abecu-
la iza ion wi h educed sys olic unc ion (LVEF 35%) and no LGE in
ca diac magne ic esonance in p oband’s younge sis e . She was im-
plan ed wi h an ICD in p ima y p e en ion. Res ing and exe cise
ECGs showed equen PVCs om he igh ao ic cusp. Ca he e abla-
ion o he igh ao ic cusp esul ed in no ecu ence a he 3 and 9
mon hs ollow-up. Addi ionally, she has a bicuspid ao ic al e (BAV)
wi hou ele an dys unc ion and disc e e, non-p og essi e ao ic dila-
ion (max. 37 mm–22 mm/m
2
) wi hou o he signs o synd omic ao ic
diseases.
The p oband’s a he died a he age o 68 due o e minal hea ailu e
accompanied by ecu en malignan en icula a hy hmias. He was di-
agnosed a he age o 50 wi h a combina ion o ischaemic ca diomyop-
a hy and p onounced LV hype abecula iza ion wi h educed LVEF
(30%) and wi hou al ula o ao ic disease. On es ing ECGs, equen
PVCs om he igh ao ic cusp, iden ical o his li ing daugh e , we e
documen ed. He died be o e molecula gene ic analysis was a ailable.
The p oband’s mo he died om in ac anial haemo hage a he age
o 66 yea s and had no ca diac disease o a hy hmia du ing he li e ime.
The p oband’s o sp ing ha e no a hy hmias o LV hype abecula iza-
ion. He son has BAV wi h mild ao ic dila a ion. The pa e nal cousin o
he p oband has no ca diological indings, no did his deceased mo he .
Me hods
The p oband and he a ec ed sis e we e examined by massi ely pa allel
sequencing (MPS, Sophia Gene ics, Swi ze land) using a cus omized panel
o 100 ca dio ascula genes and he Clinical Exome Solu ion ( 3.1, 4727
genes), espec i ely. Bioin o ma ic analysis was pe o med using a pipeline
in he SOPHiA DDM™ pla o m (Sophia Gene ics). To e i y copy numbe
a ia ion (CNV) indings, a ay compa a i e genomic hyb idiza ion (aCGH,
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Su eP in G3 Cus om CGH+SNP 4x180K, Agilen , USA) and mul iplex li-
ga ion p obe ampli ica ion (MLPA, P obemix P168, MRC Holland; The
Ne he lands), we e pe o med in bo h o hem.
MLPA analysis was used o seg ega ion analysis in o he li ing ela i es ( wo
heal hy o sp ing o he p oband and a heal hy pa e nal cousin (Figu e 1)).
Resul s
A CNV in ol ing dele ion o ou consecu i e exons
3–6
in he RYR2
gene was iden i ied by MPS in he p oband and he sis e . No o he a -
ian s (VUS/LP/P) we e ound in genes associa ed wi h de elopmen o
ca diomyopa hy, a hy hmias, and amilial BAV in bo h o hem. The
aCGH me hod con i med dele ion o exons 3–6 in he 1q43 egion
o a leas 92 kb (max. 92.5 kb), while MLPA con aining only he p obe
o exon 3 allowed o con i m his dele ion a leas in i s pa ial ex en .
MLPA analysis in es ed heal hy li ing ela i es excluded he pa ho-
genic a ian (Figu e 1).
Discussion
To ou knowledge, his is he i s case epo ha desc ibes a unique,
pa hogenic he e ozygous dele ion spanning exons 3, 4, 5, and 6 o he
RYR2 gene. This inding unde sco es he necessi y o CNV analysis wi h-
in MPS. Rega dless o ki used (cus om panel o clinical exome), a ou -
exon dele ion was de ec ed wi h high accu acy in each case, indica ing
he eliabili y o used MPS me hods.
MLPA is a eliable, ime-, and cos -e ec i e me hod o CNV de ec-
ion; howe e , no comme cial ki is cu en ly a ailable o he ull ange
o he RYR2 gene. The manu ac u e could conside expanding he cu -
en p oduc o e ing.
Ca diac mani es a ions in he epo ed sis e s and hei a he ( om
whom hey p esumably inhe i ed he dele ion) a e la gely consis en
wi h p e ious epo s in pa ien s wi h E3DS. Howe e , equen mono-
mo phic PVCs o igina ing in he egion o he ao ic oo we e on op
o CPVT ypical a hy hmia documen ed.
Ou gene ic indings could lead o a e ision o he p e iously p o-
posed e m E3DS
10
o a mo e gene al e m ha e lec s he ac ha
RYR2 dele ions may in ol e la ge egions o he gene beyond exon
3, esul ing in mixed s uc u al and a hy hmic pheno ypes.
Ca he e abla ion o AF and PVCs o igina ing om he ao ic oo
was e ec i e and could be conside ed o such pa ien s. Con e sely,
ou obse a ions may imply he need o a de ailed clinical and/o gen-
e ic e alua ion o LV hype abecula iza ion and he isk o li e-
h ea ening a hy hmias in pa ien s wi h equen PVCs o igina ing
om he ao ic oo . Fu he s udies and in e na ional egis ies o simi-
la cases could imp o e ou unde s anding.
Funding
This s udy was suppo ed by he Na ional Ins i u e o Resea ch o
Me abolic and Ca dio ascula Diseases (P og am EXCELES, ID P ojec
No. LX22NPO5104), Mo ol Uni e si y Hospi al, P ague (g an
00064203), and he Minis y o You h, Educa ion and Spo s o he
RYR2 exon
3–6 dele ion RYR2 exon
3–6 dele ion
RYR2 WT
I
II
III
RYR2 WT RYR2 WT
EF
B
A
(1 A
(2
C
D
Figu e 1 (A) Hype abecula iza ion in echoca diog aphy PLAX (A1) and PSAX (A2). (B) ECG wi h PVC om ao ic oo in p oband’s sis e . (C)
Documen ed bidi ec ional PVS du ing exe ion in p oband. (D) Documen ed VF in p oband’s ICD. (E) Th ee-gene a ional pedig ee wi h amilial seg-
ega ion o he RYR2 dele ion. The a ec ed indi iduals a e ma ked wi h ull ci cles/squa es. Indi iduals I. gene a ion died p io o gene ic es ing, no
DNA was a ailable. (F) G aphical ep esen a ion o he RYR2 dele ion (NM_001035) by aCGH showed a pa ial dele ion in he 1q43 egion conce ning
RYR2 exons 3–6.
2 T. S ibna e al.
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Czech Republic (g an LM2018132), unde he auspices o ERN GUARD-
Hea .
Con lic o in e es : none decla ed.
Da a a ailabili y
Da a a ailable on eques .
Re e ences
1. Giannini G, Con i A, Mamma ella S, Sc obogna M, So en ino V. The yanodine ecep-
o /calcium channel genes a e widely and di e en ially exp essed in mu ine b ain and
pe iphe al issues. J Cell Biol 1995;128:893–904.
2. Be s DM. Ca diac exci a ion-con ac ion coupling. Na u e 2002;415:198–205.
3. P io i SG, Napoli ano C, Tiso N, Memmi M, Vigna i G, Bloise R e al. Mu a ions in he
ca diac yanodine ecep o gene (hRyR2) unde lie ca echolamine gic polymo phic en-
icula achyca dia. Ci cula ion 2001;103:196–200.
4. Swan H, Piippo K, Vii asalo M, Heikkilä P, Paa onen T, Kainulainen K e al. A hy hmic
diso de mapped o ch omosome 1q42-q43 causes malignan polymo phic en icula
achyca dia in s uc u ally no mal hea s. J Am Coll Ca diol 1999;34:2035–42.
5. Bhuiyan ZA, an den Be g MP, an Tin elen JP, Bink-Boelkens MT, Wies eld AC, Alde s
M e al. Expanding spec um o human RYR2- ela ed disease: new elec oca diog aphic,
s uc u al, and gene ic ea u es. Ci cula ion 2007;116:1569–76.
6. Ohno S, Omu a M, Kawamu a M, Kimu a H, I oh H, Makiyama T e al. Exon 3 dele ion
o RYR2 encoding ca diac yanodine ecep o is associa ed wi h le en icula non-
compac ion. Eu Eu Pacing A hy hm Ca d Elec ophysiol J Wo k G oups Ca d Pacing
A hy hm Ca d Cell Elec ophysiol Eu Soc Ca diol 2014;16:1646–54.
7. Campbell MJ, Czosek RJ, Hin on RB, Mille EM. Exon 3 dele ion o yanodine ecep o
causes le en icula noncompac ion, wo sening ca echolamine gic polymo phic en-
icula achyca dia, and sudden ca diac a es . Am J Med Gene A 2015;167A:2197–200.
8. Ma jamaa A, Lai inen-Fo sblom P, Lah inen AM, Vii asalo M, Toi onen L, Kon ula K e al.
Sea ch o ca diac calcium cycling gene mu a ions in amilial en icula a hy hmias e-
sembling ca echolamine gic polymo phic en icula achyca dia. BMC Med Gene 2009;
10:12.
9. Leong IU, Sucich J, P osse DO, Skinne JR, C aw o d JR, Higgins C e al. A ay compa a-
i e genomic hyb idiza ion iden i ies a he e ozygous dele ion o exon 3 o he RYR2
gene. Ups J Med Sci 2015;120:190–7.
10. S einbe g C, Ros on TM, an de We C, Sana ani S, Chen SRW, Wilde AAM e al.
RYR2- yanodinopa hies: om calcium o e load o calcium de iciency. Eu opace 2023;
25:euad156.
No el ou -exon dele ion in yanodine ecep o gene 3
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