Left Ventricular Non-compaction: Is It Genetic?

Abstract

Left ventricular non-compaction (LVNC) is reported to affect 0.14 % of the pediatric population. The etiology is heterogeneous and includes a wide number of genetic causes. As an illustration, we report two patients with LVNC who were diagnosed with a genetic syndrome. We then review the literature and suggest a diagnostic algorithm to evaluate individuals with LVNC. Case 1 is a 15-month-old girl who presented with hypotonia, global developmental delay, congenital heart defect (including LVNC) and facial dysmorphism. Case 2 is a 7-month-old girl with hypotonia, seizures, laryngomalacia and LVNC. We performed chromosomal microarray for both our patients and detected chromosome 1p36 microdeletion. We reviewed the literature for other genetic causes of LVNC and formulated a diagnostic algorithm, which includes assessment for syndromic disorders, inborn error of metabolism, copy number variants and non-syndromic monogenic disorder associated with LVNC. LVNC is a relatively newly recognized entity, with heterogeneity in underlying etiology. For a systematic approach of evaluating the underlying cause to improve clinical care of these patients, a diagnostic algorithm for genetic evaluation of patients with LVNC is proposed.

Full text

REVIEW ARTICLE
Left Ventricular Non-compaction: Is It Genetic?
Teck Wah Ting
1,2
•Saumya Shekhar Jamuar
1,2
•Maggie Siewyan Brett
3
•
Ee Shien Tan
1,2
•Breana Wen Min Cham
1
•Jiin Ying Lim
1
•Hai Yang Law
2,4
•
Ene Choo Tan
3
•Jonathan Tze Liang Choo
2,5
•Angeline Hwei Meeng Lai
1,2
Received: 13 April 2015 / Accepted: 13 June 2015
ÓSpringer Science+Business Media New York 2015
Abstract Left ventricular non-compaction (LVNC) is
reported to affect 0.14 % of the pediatric population. The
etiology is heterogeneous and includes a wide number of
genetic causes. As an illustration, we report two patients
with LVNC who were diagnosed with a genetic syndrome.
We then review the literature and suggest a diagnostic
algorithm to evaluate individuals with LVNC. Case 1 is a
15-month-old girl who presented with hypotonia, global
developmental delay, congenital heart defect (including
LVNC) and facial dysmorphism. Case 2 is a 7-month-old
girl with hypotonia, seizures, laryngomalacia and LVNC.
We performed chromosomal microarray for both our
patients and detected chromosome 1p36 microdeletion. We
reviewed the literature for other genetic causes of LVNC
and formulated a diagnostic algorithm, which includes
assessment for syndromic disorders, inborn error of meta-
bolism, copy number variants and non-syndromic mono-
genic disorder associated with LVNC. LVNC is a relatively
newly recognized entity, with heterogeneity in underlying
etiology. For a systematic approach of evaluating the
underlying cause to improve clinical care of these patients,
a diagnostic algorithm for genetic evaluation of patients
with LVNC is proposed.
Keywords 1p36 Deletion syndrome Left ventricular
non-compaction Developmental delay Review of genetic
etiology Diagnostic algorithm
Introduction
Left ventricular non-compaction (LVNC), also known as
‘‘spongy’’ myocardium, is a form of cardiomyopathy,
which is characterized by prominent left ventricular tra-
beculae, and deep intertrabecular recesses. It was first
described in 1932 but only recently, in 2006, classified as a
distinct form of primary genetic cardiomyopathy by the
American Heart Association [23,42]. The prevalence of
LVNC in children is reported to be 0.14 % [33]. LVNC is
commonly diagnosed on two-dimensional (2D) echocar-
diography and either can exist in isolation or coexist with
other structural heart disease. Complications related to
LVNC can include congestive cardiac failure, arrhythmia
and thromboembolic events.
The genetic etiology of LVNC is heterogeneous [8,10,
44]. LVNC has been described in both sporadic and
familial forms. In the familial form, inheritance can be
autosomal recessive, autosomal dominant or sex linked.
Prompt and accurate diagnosis will be important for
anticipatory management of associated medical problems
and for counseling of recurrence risk in the family. How-
ever, the extent of genetic evaluation that needs to be
performed to delineate the etiology remains a clinical
challenge.
&Saumya Shekhar Jamuar
saumya.s.jamuar@kkh.com.sg
1
Genetics Service, Department of Paediatrics, KK Women’s
and Children’s Hospital, 100 Bukit Timah Road,
Singapore 229899, Singapore
2
Singhealth Duke-NUS Paediatrics Academic Clinical
Programme, Singapore, Singapore
3
KK Research Centre, KK Women’s and Children’s Hospital,
Singapore, Singapore
4
DNA Diagnostic and Research Laboratory, KK Women’s and
Children’s Hospital, Singapore, Singapore
5
Cardiology Service, Department of Paediatric Subspecialties,
KK Women’s and Children’s Hospital, Singapore, Singapore
123
Pediatr Cardiol
DOI 10.1007/s00246-015-1222-5

As an illustration, we describe two patients with LVNC
who were referred to our genetics clinic for evaluation. A
diagnosis of LVNC was made in these two patients as the
ratio of left ventricular non-compacted to compacted
myocardium was [2:1 in end systole on 2D echocardiog-
raphy. Subsequent genetic work up revealed that both
patients had 1p36 microdeletion syndrome, a rare but
known cause of LVNC. In the subsequent sections of this
report, we evaluate the literature for all reported genetic
causes of LVNC and aim to propose a diagnostic approach
for genetic evaluation of children with LVNC.
Case Illustration
Case 1
Case 1 is the second child of non-consanguineous parents
of Malay descent with no significant family history of
congenital heart defects or developmental delay. Antenatal
history was unremarkable. She was born full term via
normal vaginal delivery. Her birth weight was 2580 gm
(3rd–10th percentile), length was 46 cm (3rd percentile)
and head circumference was 31 cm (3rd percentile). There
were no immediate postnatal complications, and she was
discharged home on day 2 of life. She presented to our
hospital at 4 months of age with poor weight gain. On
examination, she was noted to be in congestive cardiac
failure. She was tachypneic and tachycardic. A continuous
murmur was heard over left infraclavicular region. The
apex beat was displaced, and she had hepatomegaly.
Echocardiography showed a large patent ductus arteriosus
(PDA) with a dilated left heart. She underwent surgical
closure of the PDA when she was 5 months old. Repeat
echocardiogram (22 days postligation) showed LVNC and
dilated cardiomyopathy, and she was started on diuretics.
On subsequent follow-up, she was noted to have
developmental delay and hypotonia and was referred to the
genetics clinic for further evaluation. On examination (at
8 months), her weight was 5.97 kg (0.3 kg below 3rd
percentile), height was 63.6 cm (0.5 cm below 3rd per-
centile) and head circumference was 39.5 cm (1 cm below
3rd percentile). She was noted to have minor facial
anomalies, including deep set eyes and midface hypoplasia,
but not suggestive of any specific syndromic diagnosis.
Cardiac examination revealed normal first and second heart
sounds with a soft ejection systolic murmur at the left
sternal edge. Respiratory and abdominal examinations
were normal. Neurological examination revealed hypotonia
but normal reflexes. Her developmental age was assessed
to be around 5 months. She developed seizures at 1 year
old; electroencephalography showed multifocal spikes, and
MRI brain showed right subependymal heterotopia. At her
last review at 15 months old, her height was 74 cm
(10–25th percentile), weight was 8.4 kg (10–25th per-
centile) and head circumference was 40 cm (3 cm less than
3rd percentile). Her karyotype was normal.
Case 2
Case 2 is the first child of non-consanguineous parents of
Chinese descent with no significant family history of
congenital heart defects or developmental delay. There
were no concerns during the initial antenatal period, but at
37 weeks of gestation, fetal movement was decreased. A
fetal ultrasound showed cardiomegaly and an emergency
lower segment cesarean section was performed. Her birth
weight was 2900 gm (50th percentile), length was 47 cm
(10th percentile) and head circumference was 34 cm (50th
percentile). APGAR scores were 5 and 7 at 1 and 5 min
after birth, respectively. She was resuscitated and intubated
at birth for persistent hypoxia. On echocardiography per-
formed for poor oxygen saturation, she was diagnosed to
have persistent pulmonary hypertension and PDA. She was
Fig. 1 Schematic diagram showing the chromosomal microdeletion (in red square) for case 1 and case 2. Deletion of PRDM16 (in red circle)
has been reported to lead to LVNC
Pediatr Cardiol
123

treated for presumed sepsis and discharged after 1 week.
She was readmitted at 2 weeks of age for respiratory dis-
tress. Repeat echocardiography (at 2 weeks old) showed
biventricular hypertrophy, a small PDA and a normal
biventricular contractility with a fractional shortening of
29.7 %. Blood alpha glucosidase level (to exclude Pompe
disease) and inborn error of metabolism screening (plasma
amino acid, plasma acylcarnitine profile, plasma lactate
and urine organic acid) were normal. On serial echocar-
diography, she was found to have LVNC at 2 months old.
At 3 months old, she developed generalized seizures. She
was also found to have hypotonia and head lag. She had no
dysmorphic features. Analysis of blood and cerebrospinal
fluid showed no evidence of infection or inborn error of
metabolism. Electroencephalography (EEG) showed
epileptiform activity. MRI brain showed no significant
abnormality. MRI heart done in the same setting confirmed
LVNC. Other medical problems include laryngomalacia
which required laser laryngoplasty as well as obstructive
sleep apnea which required noninvasive positive pressure
ventilation. Patient is now 7 months old with growth
parameters at 50th percentile. She still has mild motor
delay. She does not have arrhythmia or cardiac failure. Her
karyotype was normal.
Table 1 Comparison of
phenotype of patients with 1p36
deletion syndrome described in
the literature with our patients
Clinical features Battaglia et al. [4]. Patient 1 Patient 2
Craniofacial features
Microbrachycephaly 39/60 (65 %) ?-
Large, late closing anterior fontanelle 30/39 (77 %) --
Straight eye brows 60/60 (100 %) --
Deep set eyes 60/60 (100 %) ?-
Epicanthus 30/60 (50 %) --
Broad nasal root/bridge 60/60 (100 %) ?-
Midface hypoplasia 60/60 (100 %) ?-
Posteriorly rotated/low set/abnormal ears 20/60 (40 %) ?-
Long philtrum 60/60 (100 %) --
Pointed chin 60/60 (100 %) --
Limbs/skeletal defects
Brachydactyly/camptodactyly 48/60 (80 %) --
Short feet 48/60 (80 %) --
Skeletal anomalies 13/32 (41 %) -–
Visceral anomalies
Congenital heart defects 34/48 (71 %) ?-
Non-compaction cardiomyopathy 11/48 (23 %) ??
Dilated cardiomyopathy 2/48 (4 %) ?-
Gastrointestinal anomalies 5/18 (28 %) --
Anal anomalies 2/60 (3 %) --
Genitourinary tract defects
Renal abnormalities 4/18 (22 %) -Not checked
External genitalia abnormalities 15/60 (25 %) --
Neurological findings
Congenital hypotonia 57/60 (95 %) ??
Seizures 26/60 (44 %) ??
EEG abnormalities 34/34 (100 %) ??
Brain abnormalities 43/49 (88 %) ?-
Vision problems 23/44 (52 %) -–
Visual inattention 28/44 (64 %) --
Sensorineural deafness 9/32 (28 %) --
Development findings
Developmental delay 60/60 (100 %) ??
Mental retardation 52/60 (87 %) ?N.A.
Poor/absent expressive language 60/60 (100 %) ?N.A.
Behavioral disorders 28/60 (47 %) --
Pediatr Cardiol
123

Results
Chromosomal microarray analysis (CMA) was carried out
using the Agilent 4 9180 K CGH ?SNP catalogue array
(Agilent Technologies Inc, Santa Clara, CA, USA).
Genomic DNA from both patients was hybridized against
the Agilent Euro Female reference. Data were scanned at a
resolution of 5 land analyzed with the Agilent
Cytogenomics software version 2.5 using the ADM-2 set-
ting which provides a practical average resolution of 50 kb.
Case 1 had a loss of 3.49 Mb at Chromosome 1p36 (Chr1:
746,608–4,240,206 bp), while Case 2 had a loss of 3.4 Mb
at Chromosome 1p36 (Chr1:746,608–4,144,742 bp) (both
coordinates in GRCh37/hg19) (Fig. 1). These findings on
CMA are consistent with the diagnosis of 1p36 microdele-
tion syndrome.
Fig. 2 Clinical approach of an
individual with left ventricular
non-compaction (LVNC)
Pediatr Cardiol
123

Discussion
Here, we describe two individuals with LVNC in association
with developmental delay who were subsequently diagnosed
with 1p36 microdeletion syndrome. 1p36 microdeletion
syndrome is one of the commoner microdeletion syndromes
and has a reported incidence of 1:5000–1:10,000 [35]. It is
caused by loss of genetic material at the terminal band on the
short arm of chromosome 1. The majority of patients have
distinctive facies (deep set eyes, straight eyebrows, long
philtrum, small chin and posteriorly rotated ears), hypotonia,
learning difficulties, seizures, visual and hearing problems
and congenital anomalies involving multiple organs includ-
ing congenital heart defects such as LVNC (Table 1)[4].
There are recent reports that facial dysmorphism in children
with 1p36 deletion syndrome can be mild and variable [36]
as was the case in both our patients. Patients with 1p36
microdeletion syndrome need long-term medical follow-up.
Over time, some show improvement in motor milestones,
social interaction and adaptive behavior [4]. The cytogenetic
aberration is typically detected on CMA, although in some
individuals, the deletion is large enough to be picked up on
conventional karyotype.
LVNC has been reported to be present in 23 % of patients
in cohort studies of 1p36 deletion syndrome [4]. Mutations in
or deletions involving PRDM16 gene (OMIM#605557),
located at 1p36.32, have been implicated as a cause of both
LVNC and dilated cardiomyopathy. Disruption of PRDM16
impairs proliferative capacity during cardiogenesis. Model-
ing of PRDM16 haploinsufficiency in zebra fish resulted in
both contractile dysfunction and uncoupling of cardiomy-
ocytes, which could result in LVNC [3]. In both our patients,
their deletions involved PRDM16 (Fig. 1).
Beyond 1p36 microdeletion syndrome, other etiologies
for LVNC in children can be divided into 4 groups: syn-
dromic disorders, inborn errors of metabolism (IEM),
monogenic disorders and environmental causes. In a child
who is diagnosed with LVNC, it is important to investigate
the underlying cause as some of the conditions are poten-
tially treatable. For others, establishing a diagnosis allows
for gene/diagnosis specific surveillance and anticipatory
management for associated medical problems. Finally,
diagnosing the underlying condition enables more accurate
genetic counseling for the family.
Table 2 Syndromes and copy number variants (CNV) associated
with LVNC
Syndromes associated with aneuploidies
Turner syndrome [1,43]
Trisomy 21 [27]
Trisomy 18 [5]
Trisomy 13 [25]
Syndromes associated with copy number variations
Velocardiofacial syndrome [21,29]
1p36 deletion syndrome [4]
Syndromes associated with neuromuscular diseases
Duchenne muscular dystrophy; Becker muscular dystrophy
[17,38]
Limb girdle muscular dystrophy [20]
Multiminicore disease [37]
Other syndromes
Sotos syndrome [24]
Marfan syndrome [18]
Noonan syndrome [2]
LEOPARD syndrome [19]
Cornelia De Lange syndrome [9]
Roifman syndrome [22]
Hypomelanosis of Ito [8]
Nail patella syndrome [12]
Other CNV
8p23.1 deletion [6]
Trisomic for the 4q31 ?qter region and monosomic for the
1q43 ?1qter [7,41]
1q43 deletion [15]
Distal 5q deletion [28]
Table 3 Inborn errors of metabolism associated with LVNC
Gene Phenotype
Barth syndrome [16]TAZ at Xq28 Proximal myopathy, ventricular arrhythmia, neonatal
hypoglycemia, neutropenia, urinary excretion of
3-methylglutaconic acid
GSD type 1b [13]G6PC at 17q21 Hypoglycemia, hepatomegaly, neutropenia
Malonyl coenzyme A decarboxylase
deficiency [30]
MLYCD at 16q24 Hypoglycemia, metabolic acidosis, developmental delay
Cobalamin C deficiency [39]MMACHC at 1p34.1 Global developmental delay, failure to thrive, cytopenia,
increased urinary excretion of methylmalonic acid, metabolic
acidosis with high ketones, high homocysteine
Mitochondrial disorder [11,31] Heterogeneous Multisystem involvement, lactic acidosis
Pediatr Cardiol
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Firstly, a child diagnosed with LVNC should be evalu-
ated for signs of complications such as heart failure,
arrhythmia and thromboembolism (Fig. 2). The presence of
acute symptoms like chest pain and dyspnea will need to be
looked into urgently. Myocardial ischemia and myocarditis
will need to be excluded with ECG, cardiac enzymes and
urgent echocardiography. These complications will need
urgent attention and intervention. Other information which
should be gathered include if LVNC coexists with other
form of heart defects or cardiomyopathy. Family history of
LVNC should be elucidated, and screening echocardiog-
raphy for first degree relatives should be considered.
Subsequent evaluation should include assessment for
genetic syndromes. Examination should focus on assess-
ment for craniofacial dysmorphism, proximal myopathy
and learning disability (Table 2). If a specific genetic
syndrome is recognized, confirmation of the syndrome via
confirmatory testing should be performed. If no genetic
syndrome is identified, investigations to look for abnor-
malities related to IEM should be considered next. Meta-
bolic acidosis, lactic acidosis and/or abnormal urine
organic acid results would suggest a diagnosis of an IEM.
Clinical suspicion of IEM can be confirmed by enzyme
testing or genetic testing (Table 3).
If no specific diagnosis of genetic syndrome or inborn
error of metabolism is apparent, CMA to look for
microdeletion or microduplication syndromes is the next
suggested step. CMA can detect genetic imbalances in
patients with greater resolution than conventional kary-
otyping (Table 2). The implications of these changes, also
known as copy number variants (CNV), will depend on the
region of these CNV. Digilio et al. [8] reported that in a
group of 25 patients with syndromic LVNC, diagnosis was
made with standard chromosome analysis and subtelomeric
fluorescent in situ hybridization in seven patients.
Microarray analysis in the remaining patients detected two
patients with pathogenic CNV. The overall diagnostic yield
of the combination of all the methods was one-third of this
cohort of patients with syndromic LVNC.
If no pathogenic variant is identified on CMA, massively
parallel sequencing (MPS) of candidate genes can be
considered to detect monogenic disorders (Table 4).
Schaefer et al. [32] reported a case of an infant with severe
LVNC with compound heterozygous mutations in the
Table 4 Monogenic disorders associated with LVNC
Phenotype (OMIM ID) Gene Chromosome location (hg19) Additional phenotype
LVNC1 (604169) DTNA Ch18:32,073,253–32,471,807 Prominent endomyocardial trabeculations
LVNC2 (609470) No candidate
gene identified
Ch11:0–21,700,000 Nil
LVNC3 (601493) LDB3 Ch10:88,426,541–88,495,828 Nil
LVNC4 (613424) ACTC1 Ch15:35,080,296–35,087,926 Dilated cardiomyopathy
Ventricular hypertrophy(some)
Restrictive cardiomyopathy (some)
Ventricular arrhythmia (some)
LVNC5 (613426) MYH7 Ch14:23,881,946–23,904,869 Pulmonary artery hypoplasia (some)
Left ventricular dilatation
CCF
LVNC6 (601494) TNNT2 Ch1:201,328,135–201,346,835 Left ventricular dilation
Congestive heart failure
Sudden death
Myocyte hypertrophy
LVNC7 (615092) MIB1 Ch18:19,321,289–19,450,917 Nil
LVNC8 (615373) PDRM16 Ch1:2,985,564–3,355,184 Left ventricular dysfunction
LVNC9 (611878) TPM1 Ch15:63,334,837–63,364,113 Dilated cardiomyopathy
LVNC10 (615396) MYBPC3 Ch11:47,352,956–47,374,252 Cardiomyopathy, dilated
Heart failure, progressive and sometimes fatal
Ventricular flutter, non-sustained (in some patients)
N.A. SCN5A [34] Ch3:38,589,552–38,691,163 Arrhythmia
N.A. LMNA [14] Ch1:156,052,368–156,109,879 Dilated cardiomyopathy
Long QT Syndrome [26] Heterogeneous Long corrected QT interval, Torsade de pointes
or T wave alternans on ECG; syncope during
physical exertion
Pediatr Cardiol
123

MYBPC3 gene identified by MPS within 3 days. The
diagnosis enabled screening for other family members and
genetic counseling. In a laboratory providing diagnostic
services for LVNC for associated genes by MPS, clinically
significant variants were detected in 24 % of 108 broadly
referred individuals with LVNC. Variants were present in
MYH7 (13.6 %), MYBPC3(4.0 %), TNNI3 (2.0 %), VCL
(2.8 %), TAZ (1.1 %) and TNNT2 (1.0 %) [40]. With
advancement in techniques of molecular genetic investi-
gations, more genetic mutations associated with LVNC can
be identified.
Conclusion
Left ventricular non-compaction in children is a form of
cardiomyopathy that warrants investigations into the
underlying etiology. LVNC is heterogeneous in its genetic
etiologies. Identification of the underlying genetic aberra-
tions is important to understand the pathophysiology of
LVNC, to plan for surveillance for associated medical
problems as well as to enable genetic counseling and
prenatal testing for affected families.
Acknowledgments We thank the patients and their families
reported herein for their participation in this research.
Compliance with Ethical Standards
Conflict of interest None.
References
1. Altenberger H, Stollberger C, Finsterer J (2009) Isolated left
ventricular hypertrabeculation/noncompaction in a Turner mosaic
with male phenotype. Acta Cardiol 64(1):99–103
2. Amann G, Sherman FS (1992) Myocardial dysgenesis with per-
sistent sinusoids in a neonate with Noonan’s phenotype. Pediatr
Pathol 12(1):83–92
3. Arndt AK, Schafer S, Drenckhahn JD, Sabeh MK, Plovie ER,
Caliebe A, Klopocki E, Musso G, Werdich AA, Kalwa H, Heinig
M, Padera RF, Wassilew K, Bluhm J, Harnack C, Martitz J,
Barton PJ, Greutmann M, Berger F, Hubner N, Siebert R, Kramer
HH, Cook SA, MacRae CA, Klaassen S (2013) Fine mapping of
the 1p36 deletion syndrome identifies mutation of PRDM16 as a
cause of cardiomyopathy. Am J Hum Genet 93(1):67–77. doi:10.
1016/j.ajhg.2013.05.015
4. Battaglia A, Hoyme HE, Dallapiccola B, Zackai E, Hudgins L,
McDonald-McGinn D, Bahi-Buisson N, Romano C, Williams
CA, Brailey LL, Zuberi SM, Carey JC (2008) Further delineation
of deletion 1p36 syndrome in 60 patients: a recognizable phe-
notype and common cause of developmental delay and mental
retardation. Pediatrics 121(2):404–410. doi:10.1542/peds.2007-
0929
5. Beken S, Cevik A, Turan O, Hirfanoglu IM, Unal S, Altuntas N,
Pektas A, Turkyilmaz C, Tunaoglu S (2011) A neonatal case of
left ventricular noncompaction associated with trisomy 18. Genet
Couns 22(2):161–164
6. Blinder JJ, Martinez HR, Craigen WJ, Belmont J, Pignatelli RH,
Jefferies JL (2011) Noncompaction of the left ventricular myo-
cardium in a boy with a novel chromosome 8p23.1 deletion. Am J
Med Genet A 155A(9):2215–2220. doi:10.1002/ajmg.a.34129
7. De Rosa G, Pardeo M, Bria S, Caresta E, Vasta I, Zampino G,
Zollino M, Zuppa AA, Piastra M (2005) Isolated myocardial non-
compaction in an infant with distal 4q trisomy and distal 1q
monosomy. Eur J Pediatr 164(4):255–256. doi:10.1007/s00431-
005-1620-4
8. Digilio MC, Bernardini L, Gagliardi MG, Versacci P, Baban A,
Capolino R, Dentici ML, Roberti MC, Angioni A, Novelli A,
Marino B, Dallapiccola B (2013) Syndromic non-compaction of
the left ventricle: associated chromosomal anomalies. Clin Genet
84(4):362–367. doi:10.1111/cge.12069
9. Fazio G, Pipitone S, Iacona MA, Marchi S, Mongiovi M, Zito R,
Sutera L, Novo S (2007) The noncompaction of the left ven-
tricular myocardium: our paediatric experience. J Cardiovasc
Med 8(11):904–908. doi:10.2459/JCM.0b013e32801462b0
10. Finsterer J (2009) Cardiogenetics, neurogenetics, and patho-
genetics of left ventricular hypertrabeculation/noncompaction.
Pediatr Cardiol 30(5):659–681. doi:10.1007/s00246-008-9359-0
11. Finsterer J, Stollberger C (1998) Hypertrabeculated left ventricle
in mitochondriopathy. Heart 80(6):632
12. Finsterer J, Stollberger C, Kopsa W (2003) Noncompaction on
cardiac MRI in a patient with nail-patella syndrome and mito-
chondriopathy. Cardiology 100(1):48–49. doi:10.1159/000072
393
13. Goeppert B, Lindner M, Vogel MN, Warth A, Stenzinger A,
Renner M, Schnabel P, Schirmacher P, Autschbach F, Weichert
W (2012) Noncompaction myocardium in association with type
Ib glycogen storage disease. Pathol Res Pract 208(10):620–622.
doi:10.1016/j.prp.2012.06.007
14. Hermida-Prieto M, Monserrat L, Castro-Beiras A, Laredo R,
Soler R, Peteiro J, Rodriguez E, Bouzas B, Alvarez N, Muniz J,
Crespo-Leiro M (2004) Familial dilated cardiomyopathy and
isolated left ventricular noncompaction associated with lamin
A/C gene mutations. Am J Cardiol 94(1):50–54. doi:10.1016/j.
amjcard.2004.03.029
15. Kanemoto N, Horigome H, Nakayama J, Ichida F, Xing Y,
Buonadonna AL, Kanemoto K, Gentile M (2006) Interstitial
1q43-q43 deletion with left ventricular noncompaction myo-
cardium. Eur J Med Genet 49(3):247–253. doi:10.1016/j.ejmg.
2005.06.004
16. Karkucinska-Wieckowska A, Trubicka J, Werner B, Kokoszyn-
ska K, Pajdowska M, Pronicki M, Czarnowska E, Lebiedzinska
M, Sykut-Cegielska J, Ziolkowska L, Jaron W, Dobrzanska A,
Ciara E, Wieckowski MR, Pronicka E (2013) Left ventricular
noncompaction (LVNC) and low mitochondrial membrane
potential are specific for Barth syndrome. J Inher Metab Dis
36(6):929–937. doi:10.1007/s10545-013-9584-4
17. Kimura K, Takenaka K, Ebihara A, Uno K, Morita H, Nakajima T,
Ozawa T, Aida I, Yonemochi Y, Higuchi S, Motoyoshi Y, Mikata
T, Uchida I, Ishihara T, Komori T, Kitao R, Nagata T, Takeda S,
Yatomi Y, Nagai R, Komuro I (2013) Prognostic impact of left
ventricular noncompaction in patients with Duchenne/Becker
muscular dystrophy—prospective multicenter cohort study. Int J
Cardiol 168(3):1900–1904. doi:10.1016/j.ijcard.2012.12.058
18. Kwiatkowski D, Hagenbuch S, Meyer R (2010) A teenager with
Marfan syndrome and left ventricular noncompaction. Pediatr
Cardiol 31(1):132–135. doi:10.1007/s00246-009-9552-9
19. Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A,
Elliott P, Versacci P, Calabro P, De Zorzi A, Di Salvo G, Syrris
P, Patton M, McKenna WJ, Dallapiccola B, Calabro R (2007)
Prevalence and clinical significance of cardiovascular abnor-
malities in patients with the LEOPARD syndrome. Am J Cardiol
100(4):736–741. doi:10.1016/j.amjcard.2007.03.093
Pediatr Cardiol
123

20. Lofiego C, Biagini E, Pasquale F, Ferlito M, Rocchi G, Perugini E,
Bacchi-Reggiani L, Boriani G, Leone O, Caliskan K, ten Cate FJ,
Picchio FM, Branzi A, Rapezzi C (2007) Wide spectrum of pre-
sentation and variable outcomes of isolated left ventricular non-
compaction. Heart 93(1):65–71. doi:10.1136/hrt.2006.088229
21. Madan S, Madan-Khetarpal S, Park SC, Surti U, Bailey AL,
McConnell J, Tadros SS (2010) Left ventricular non-compaction
on MRI in a patient with 22q11.2 distal deletion. Am J Med
Genet A 152A(5):1295–1299. doi:10.1002/ajmg.a.33367
22. Mandel K, Grunebaum E, Benson L (2001) Noncompaction of
the myocardium associated with Roifman syndrome. Cardiol
Young 11(2):240–243
23. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D,
Arnett D, Moss AJ, Seidman CE, Young JB, American Heart A,
Council on Clinical Cardiology HF, Transplantation C, Quality of
C, Outcomes R, Functional G, Translational Biology Interdisci-
plinary Working G, Council on E, Prevention (2006) Contem-
porary definitions and classification of the cardiomyopathies: an
American Heart Association Scientific Statement from the
Council on Clinical Cardiology, Heart Failure and Transplanta-
tion Committee; Quality of Care and Outcomes Research and
Functional Genomics and Translational Biology Interdisciplinary
Working Groups; and Council on Epidemiology and Prevention.
Circulation 113(14):1807–1816. doi:10.1161/CIRCULATIO
NAHA.106.174287
24. Martinez HR, Belmont JW, Craigen WJ, Taylor MD, Jefferies
JL (2011) Left ventricular noncompaction in Sotos syndrome.
Am J Med Genet Part A 155(5):1115–1118. doi:10.1002/ajmg.a.
33838
25. McMahon CJ, Chang AC, Pignatelli RH, Miller-Hance WC, Eble
BK, Towbin JA, Denfield SW (2005) Left ventricular noncom-
paction cardiomyopathy in association with trisomy 13. Pediatr
Cardiol 26(4):477–479. doi:10.1007/s00246-004-0788-0
26. Nakashima K, Kusakawa I, Yamamoto T, Hirabayashi S, Hosoya
R, Shimizu W, Sumitomo N (2013) A left ventricular noncom-
paction in a patient with long QT syndrome caused by a KCNQ1
mutation: a case report. Heart Vessels 28(1):126–129. doi:10.
1007/s00380-012-0235-8
27. Patil MB, Patil SM (2013) Left-ventricular noncompaction in an
infant with trisomy 21. Pediatr Cardiol 34(3):722–724. doi:10.
1007/s00246-012-0330-8
28. Pauli RM, Scheib-Wixted S, Cripe L, Izumo S, Sekhon GS
(1999) Ventricular noncompaction and distal chromosome 5q
deletion. Am J Med Genet 85(4):419–423
29. Pignatelli RH, McMahon CJ, Dreyer WJ, Denfield SW, Price J,
Belmont JW, Craigen WJ, Wu J, El Said H, Bezold LI, Clunie S,
Fernbach S, Bowles NE, Towbin JA (2003) Clinical characteri-
zation of left ventricular noncompaction in children: a relatively
common form of cardiomyopathy. Circulation 108(21):2672–
2678. doi:10.1161/01.CIR.0000100664.10777.B8
30. Prada CE, Jefferies JL, Grenier MA, Huth CM, Page KI, Spicer
RL, Towbin JA, Leslie ND (2012) Malonyl coenzyme A decar-
boxylase deficiency: early dietary restriction and time course of
cardiomyopathy. Pediatrics 130(2):e456–e460. doi:10.1542/peds.
2011-2927
31. Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EO,
Neish SR, Ware SM, Hunter JV, Fernbach SD, Vladutiu GD,
Wong LJ, Vogel H (2004) Clinical spectrum, morbidity, and
mortality in 113 pediatric patients with mitochondrial disease.
Pediatrics 114(4):925–931. doi:10.1542/peds.2004-0718
32. Schaefer E, Helms P, Marcellin L, Desprez P, Billaud P,
Chanavat V, Rousson R, Millat G (2014) Next-generation
sequencing (NGS) as a fast molecular diagnosis tool for left
ventricular noncompaction in an infant with compound mutations
in the MYBPC3 gene. Eur J Med Genet 57(4):129–132. doi:10.
1016/j.ejmg.2014.02.015
33. Sert A, Aypar E, Aslan E, Odabas D (2013) Isolated right ven-
tricular noncompaction in a newborn. Pediatr Cardiol
34(8):1896–1898. doi:10.1007/s00246-012-0435-0
34. Shan L, Makita N, Xing Y, Watanabe S, Futatani T, Ye F, Saito
K, Ibuki K, Watanabe K, Hirono K, Uese K, Ichida F, Miyawaki
T, Origasa H, Bowles NE, Towbin JA (2008) SCN5A variants in
Japanese patients with left ventricular noncompaction and
arrhythmia. Mol Genet Metab 93(4):468–474
35. Shapira SK, McCaskill C, Northrup H, Spikes AS, Elder FF,
Sutton VR, Korenberg JR, Greenberg F, Shaffer LG (1997)
Chromosome 1p36 deletions: the clinical phenotype and molec-
ular characterization of a common newly delineated syndrome.
Am J Hum Genet 61(3):642–650. doi:10.1086/515520
36. Shimada S, Shimojima K, Okamoto N, Sangu N, Hirasawa K,
Matsuo M, Ikeuchi M, Shimakawa S, Shimizu K, Mizuno S,
Kubota M, Adachi M, Saito Y, Tomiwa K, Haginoya K, Numabe
H, Kako Y, Hayashi A, Sakamoto H, Hiraki Y, Minami K,
Takemoto K, Watanabe K, Miura K, Chiyonobu T, Kumada T,
Imai K, Maegaki Y, Nagata S, Kosaki K, Izumi T, Nagai T,
Yamamoto T (2014) Microarray analysis of 50 patients reveals
the critical chromosomal regions responsible for 1p36 deletion
syndrome-related complications. Brain Dev. doi:10.1016/j.brain
dev.2014.08.002
37. Simsek Z, Acar G, Akcakoyun M, Esen O, Emiroglu Y, Esen AM
(2012) Left ventricular noncompaction in a patient with multi-
minicore disease. J Cardiovasc Med 13(10):660–662. doi:10.
2459/JCM.0b013e32833cdcd0
38. Statile CJ, Taylor MD, Mazur W, Cripe LH, King E, Pratt J,
Benson DW, Hor KN (2013) Left ventricular noncompaction in
Duchenne muscular dystrophy. J Cardiovasc Magn Reson 15:67.
doi:10.1186/1532-429X-15-67
39. Tanpaiboon P, Sloan JL, Callahan PF, McAreavey D, Hart PS,
Lichter-Konecki U, Zand D, Venditti CP (2013) Noncompaction
of the ventricular myocardium and hydrops fetalis in cobalamin C
disease. JIMD Rep 10:33–38. doi:10.1007/8904_2012_197
40. Teekakirikul P, Kelly MA, Rehm HL, Lakdawala NK, Funke BH
(2013) Inherited cardiomyopathies: molecular genetics and clin-
ical genetic testing in the postgenomic era. J Mol Diagn
15(2):158–170. doi:10.1016/j.jmoldx.2012.09.002
41. Turleau C, de Grouchy J, Frezal J, Richardet JM (1983) Distal 1q
monosomy. 2 new cases and description of the syndrome. Ann
Genet 26(3):161–164
42. Udeoji DU, Philip KJ, Morrissey RP, Phan A, Schwarz ER
(2013) Left ventricular noncompaction cardiomyopathy: upda-
ted review. Ther Adv Cardiovasc Dis 7(5):260–273. doi:10.
1177/1753944713504639
43. van Heerde M, Hruda J, Hazekamp MG (2003) Severe pulmonary
hypertension secondary to a parachute-like mitral valve, with the
left superior caval vein draining into the coronary sinus, in a girl
with Turner’s syndrome. Cardiol Young 13(4):364–366
44. Zaragoza MV, Arbustini E, Narula J (2007) Noncompaction of
the left ventricle: primary cardiomyopathy with an elusive
genetic etiology. Curr Opin Pediatr 19(6):619–627. doi:10.1097/
MOP.0b013e3282f1ecbc
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