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Introduction: Left ventricular non-compaction (LVNC) represents a genetically heterogeneous cardiomyopathy which occurs in both children and adults. Its genetic spectrum overlaps with other types of cardiomyopathy. However, LVNC phenotypes in different age groups can have distinct genetic aetiologies. The aim of the study was to decipher the genetic spectrum of LVNC presented in childhood. Patient Group and Methods: Twenty patients under the age of 18 years diagnosed with LVNC were enrolled in the study. Target sequencing and whole-exome sequencing were performed using a panel of 108 cardiomyopathy-associated genes. Pathogenic, likely pathogenic, and variants of unknown significance found in genes highly expressed in cardiomyocytes were considered as variants of interest for further analysis. Results: The median age at presentation was 8.0 (0.1–17) years, with 6 patients presenting before 1 year of age. Twelve (60%) patients demonstrated reduced ejection fraction. Right ventricular (RV) dilation was registered in 6 (30%), often in combination with reduced RV contractility (25%). Almost half (45%) of the patients demonstrated biventricular involvement already at disease presentation. For pathogenic and likely pathogenic variants, the positive genotyping rate was 45%, and these variants were found mainly in non-contractile structural sarcomeric genes (ACTN2, MYPN, and TTN) or in metabolic and signal transduction genes (BRAF and TAZ). Likely pathogenic TAZ variants were detected in all 5 patients suspected of having Barth syndrome. No pathogenic or likely pathogenic variants were found in genes encoding for sarcomeric contractile proteins, but variants of unknown significance were detected in 3 out of 20 patients (MYH6, MYH7, and MYLK2). In 4 patients, variants of unknown significance in ion-channel genes were detected. Conclusion: We detected a low burden of contractile sarcomeric variants in LVNC patients presenting below the age of 18 years, with the major number of variants residing in non-contractile structural sarcomeric genes. The identification of the variants in ion-channel and related genes not previously associated with LVNC in paediatric patients requires further examination of their functional role.

1.
Stöllberger
C
,
Finsterer
J
.
Understanding left ventricular hypertrabeculation/noncompaction: pathomorphologic findings and prognostic impact of neuromuscular comorbidities
.
Expert Rev Cardiovasc Ther
.
2019
Feb
;
17
(
2
):
95
109
.
[PubMed]
1477-9072
2.
Loria
V
,
Colizzi
C
,
Vaccarella
M
,
Franceschi
F
,
Aspromonte
N
.
Left Ventricular Noncompaction: Cause or Consequence of Myocardial Disease? A Case Report and Literature Review
.
Cardiology
.
2019
;
143
(
3-4
):
100
4
.
[PubMed]
0008-6312
3.
Weiford
BC
,
Subbarao
VD
,
Mulhern
KM
.
Noncompaction of the ventricular myocardium
.
Circulation
.
2004
Jun
;
109
(
24
):
2965
71
.
[PubMed]
0009-7322
4.
Zhang
W
,
Chen
H
,
Qu
X
,
Chang
CP
,
Shou
W
.
Molecular mechanism of ventricular trabeculation/compaction and the pathogenesis of the left ventricular noncompaction cardiomyopathy (LVNC)
.
Am J Med Genet C Semin Med Genet
.
2013
Aug
;
163C
(
3
):
144
56
.
[PubMed]
1552-4868
5.
Oechslin
EN
,
Attenhofer Jost
CH
,
Rojas
JR
,
Kaufmann
PA
,
Jenni
R
.
Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis
.
J Am Coll Cardiol
.
2000
Aug
;
36
(
2
):
493
500
.
[PubMed]
0735-1097
6.
Luxán
G
,
Casanova
JC
,
Martínez-Poveda
B
,
Prados
B
,
D’Amato
G
,
MacGrogan
D
, et al
Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy
.
Nat Med
.
2013
Feb
;
19
(
2
):
193
201
.
[PubMed]
1078-8956
7.
Richard
P
,
Ader
F
,
Roux
M
,
Donal
E
,
Eicher
JC
,
Aoutil
N
, et al
Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity
.
Clin Genet
.
2019
Mar
;
95
(
3
):
356
67
.
[PubMed]
0009-9163
8.
van Waning
JI
,
Caliskan
K
,
Hoedemaekers
YM
,
van Spaendonck-Zwarts
KY
,
Baas
AF
,
Boekholdt
SM
, et al
Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy
.
J Am Coll Cardiol
.
2018
Feb
;
71
(
7
):
711
22
.
[PubMed]
0735-1097
9.
Okumura
T
,
Murohara
T
.
Unsolved Issue in Left Ventricular Noncompaction: Is the Strange Form of Myocardium Congenital or Acquired?
Cardiology
.
2019
;
143
(
3-4
):
105
6
.
[PubMed]
0008-6312
10.
Wang
C
,
Takasaki
A
,
Watanabe Ozawa
S
,
Nakaoka
H
,
Okabe
M
,
Miyao
N
, et al
Long-Term Prognosis of Patients With Left Ventricular Noncompaction - Comparison Between Infantile and Juvenile Types
.
Circ J
.
2017
Apr
;
81
(
5
):
694
700
.
[PubMed]
1346-9843
11.
Pignatelli
RH
,
McMahon
CJ
,
Dreyer
WJ
,
Denfield
SW
,
Price
J
,
Belmont
JW
, et al
Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy
.
Circulation
.
2003
Nov
;
108
(
21
):
2672
8
.
[PubMed]
0009-7322
12.
Stöllberger
C
,
Gerecke
B
,
Engberding
R
,
Grabner
B
,
Wandaller
C
,
Finsterer
J
, et al
Interobserver Agreement of the Echocardiographic Diagnosis of LV Hypertrabeculation/Noncompaction
.
JACC Cardiovasc Imaging
.
2015
Nov
;
8
(
11
):
1252
7
.
[PubMed]
1936-878X
13.
Jenni
R
,
Oechslin
E
,
Schneider
J
,
Attenhofer Jost
C
,
Kaufmann
PA
.
Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy
.
Heart
.
2001
Dec
;
86
(
6
):
666
71
.
[PubMed]
1355-6037
14.
Petersen
SE
,
Selvanayagam
JB
,
Wiesmann
F
,
Robson
MD
,
Francis
JM
,
Anderson
RH
, et al
Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging
.
J Am Coll Cardiol
.
2005
Jul
;
46
(
1
):
101
5
.
[PubMed]
0735-1097
15.
Kiselev
A
,
Vaz
R
,
Knyazeva
A
,
Khudiakov
A
,
Tarnovskaya
S
,
Liu
J
, et al
De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy
.
Hum Mutat
.
2018
Sep
;
39
(
9
):
1161
72
.
[PubMed]
1059-7794
16.
Kostareva
A
,
Kiselev
A
,
Gudkova
A
,
Frishman
G
,
Ruepp
A
,
Frishman
D
, et al
Genetic Spectrum of Idiopathic Restrictive Cardiomyopathy Uncovered by Next-Generation Sequencing
.
PLoS One
.
2016
Sep
;
11
(
9
):
e0163362
.
[PubMed]
1932-6203
17.
Kiselev
A
,
Vaz
R
,
Knyazeva
A
,
Sergushichev
A
,
Dmitrieva
R
,
Khudiakov
A
, et al
Truncating Variant in Myof Gene Is Associated With Limb-Girdle Type Muscular Dystrophy and Cardiomyopathy
.
Front Genet
.
2019
Jun
;
10
:
608
.
[PubMed]
1664-8021
18.
Richards
S
,
Aziz
N
,
Bale
S
,
Bick
D
,
Das
S
,
Gastier-Foster
J
, et al;
ACMG Laboratory Quality Assurance Committee
.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
.
Genet Med
.
2015
May
;
17
(
5
):
405
24
.
[PubMed]
1098-3600
19.
Richardson
P
,
McKenna
W
,
Bristow
M
,
Maisch
B
,
Mautner
B
,
O’Connell
J
, et al
Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies
.
Circulation
.
1996
Mar
;
93
(
5
):
841
2
.
[PubMed]
0009-7322
20.
Weir-McCall
JR
,
Yeap
PM
,
Papagiorcopulo
C
,
Fitzgerald
K
,
Gandy
SJ
,
Lambert
M
, et al
Left Ventricular Noncompaction: Anatomical Phenotype or Distinct Cardiomyopathy?
J Am Coll Cardiol
.
2016
Nov
;
68
(
20
):
2157
65
.
[PubMed]
0735-1097
21.
Sedaghat-Hamedani
F
,
Haas
J
,
Zhu
F
,
Geier
C
,
Kayvanpour
E
,
Liss
M
, et al
Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy
.
Eur Heart J
.
2017
Dec
;
38
(
46
):
3449
60
.
[PubMed]
0195-668X
22.
Miszalski-Jamka
K
,
Jefferies
JL
,
Mazur
W
,
Głowacki
J
,
Hu
J
,
Lazar
M
, et al
Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction
.
Circ Cardiovasc Genet
.
2017
Aug
;
10
(
4
):
e001763
.
[PubMed]
1942-325X
23.
Cetin
MS
,
Ozcan Cetin
EH
,
Canpolat
U
,
Cay
S
,
Topaloglu
S
,
Temizhan
A
, et al
Usefulness of Fragmented QRS Complex to Predict Arrhythmic Events and Cardiovascular Mortality in Patients With Noncompaction Cardiomyopathy
.
Am J Cardiol
.
2016
May
;
117
(
9
):
1516
23
.
[PubMed]
0002-9149
24.
Zhou
H
,
Lin
X
,
Fang
L
,
Zhu
W
,
Zhao
X
,
Ding
H
, et al
Prolonged QTc indicates the clinical severity and poor prognosis in patients with isolated left ventricular non-compaction
.
Int J Cardiovasc Imaging
.
2017
Dec
;
33
(
12
):
2013
20
.
[PubMed]
1569-5794
25.
Osorio
DS
,
Gomes
ER
.
Connecting the nucleus to the cytoskeleton for nuclear positioning and cell migration
.
Adv Exp Med Biol
.
2014
;
773
:
505
20
.
[PubMed]
0065-2598
26.
Mattioli
E
,
Columbaro
M
,
Jafferali
MH
,
Schena
E
,
Hallberg
E
,
Lattanzi
G
.
Samp1 Mislocalization in Emery-Dreifuss Muscular Dystrophy
.
Cells
.
2018
Oct
;
7
(
10
):
E170
.
[PubMed]
2073-4409
27.
Sewry
CA
,
Laitila
JM
,
Wallgren-Pettersson
C
.
Nemaline myopathies: a current view
.
J Muscle Res Cell Motil
.
2019
Jun
;
40
(
2
):
111
26
.
[PubMed]
0142-4319
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