Prenatal diagnosis of feta noncompaction cardiomyopathy with de novoCALM 2 mutation: first description
Wen Zhang1,2#, Xiaohui Dai1,2#,
Hanmin Liu2,3, Lei Li2,4, Shu
Zhou2,5, Qi Zhu1,2 and Jiao
Chen1,2*
1. Department of Ultrasonic Medicine, West China Second University
Hospital of Sichuan University, Chengdu, Sichuan 610041, China
2. Key Laboratory of Birth Defects and Related Diseases of Women and
Children (Sichuan University), Ministry of Education, Chengdu, Sichuan
610041, China
3. Department of Pediatrics, West China Second University Hospital of
Sichuan University, Chengdu, Sichuan 610041, China
4. Department of Pathology, West China Second University Hospital of
Sichuan University, Chengdu, Sichuan 610041, China
5. Department of Obstetrics, West China Second University Hospital of
Sichuan University, Chengdu, Sichuan 610041, China
# These authors contributed equally to this work.
*Correspondence author, Tel/Fax: +86 28 85503744,
Email:jiaochen2000@163.com
Abstract
We report what apprears to be the first case of fetal noncompaction
cardiomyopathy in both ventricles accompanied by a mutation in the
calmodulin gene (CALM2 ): A 25-year-old woman was referred to our
hospital at 25+1 weeks of gestation for evaluation of
fetal defects. A postnatal echocardiography showed biventricular
noncompaction cardiomyopathy. After terminated the pregnancy, fetal
noncompaction cardiomyopathy was comfirmed by autopsy and
histopathologic examination. And the whole-exome sequencing of genomic
DNA demonstrated a de novo heterozygous mutation
(c.389A>G;p.D130G) in CALM2 , whereas the parents
were normal. In this case report, we highlight the gene mutation in
noncompaction cardiomyopathy.
Key words: Prenatal, Noncompaction cardiomyopathy, CALM2
1 INTRODUCTION
Noncompaction cardiomyopathy is a rare disorder that frequently
manifests as monogenic diseases, especially neuromuscular disorders and
chromosomal defects, and was first reported on autopsy in 1969 [1].
The incidence of noncompaction cardiomyopathy in the general population
ranges from 0.05% to 0.25%, whereas the incidence in children may
reach 9.2% [2]. Noncompaction cardiomyopathy is characterized by
increased numbers of prominent trabeculations and deep intertrabecular
spaces. With the development of medical imaging techniques, the
detection rate of noncompaction cardiomyopathy has increased, and the
disorder may even be recognized as early as the fetal period. We herein
present the first case of fetal noncompaction cardiomyopathy in both
ventricles accompanied by a mutation in the calmodulin gene
(CALM2 ) at 25+1 weeks of gestation.
2 CASE PRESENTATION
A 25-year-old woman (gravida 1, para 0) was referred to our hospital at
25+1 weeks of gestation for evaluation of fetal
defects. The patient was allergic to penicillin. Both parents were
healthy, and there was no family history of birth defects or exposure to
any specific teratogenic agents. A postnatal two-dimensional
ultrasonographic investigation (3.0–5.0 MHz) (Voluson E10; GE
Healthcare, Chicago, IL, USA) showed biventricular noncompaction
cardiomyopathy, slight pericardial effusion, and bradycardia (106 bpm).
The ratio of noncompacted to compacted myocardium was about 3 in the
left ventricle and about 2 in the right ventricle (Figure 1A). Color
Doppler revealed blood perfusion to the intertrabecular recesses (Figure
1B). The cardiovascular profile score was 9. Two weeks later, the fetal
heart showed no significant improvement.
The couple decided to terminate the pregnancy by inducing labor with
ethacridine lactate (Rivanol®; Fengchen Group Co.,
Ltd., Qingdao, China). The woman vaginally delivered a stillborn child 2
days later. Genomic DNA was extracted from the muscle of the fetus to
perform whole-exome sequencing. The result demonstrated a de novo
heterozygous mutation (c.389A>G;p.D130G) in CALM2(Figure 2), whereas the sequencing results of the parents were normal.
At autopsy, the biventricular wall contained increased numbers of
prominent trabeculae and deep intratrabecular recesses (Figure 3).
Histopathologic examination confirmed fetal noncompaction cardiomyopathy
(Figure 4).
3 DISCUSSION
Noncompaction is a rare cardiomyopathy with various genotypic and
phenotypic manifestations. It is categorized as a primary genetic
cardiomyopathy by the American Heart Association and as an unclassified
cardiomyopathy by the European Society of Cardiology [3]. According
to a study by Stöllberger et al. [4], the diagnostic criteria for
noncompaction cardiomyopathy by echocardiography in pregnancy are as
follows: in the end-diastolic stage, at least four trabeculations
protruding apically to the papillary muscle of the left ventricle
visible in one imaging plane; a two-layered structure with epicardial
compacted and endocardial noncompacted layers and a
noncompaction:compaction ratio of ≥2; and in color Doppler,
intraventricular blood perfusing the intertrabecular spaces.
The disorder can be familial or sporadic and may be isolated or
accompanied by other cardiac diseases. The etiology of noncompaction
cardiomyopathy is complex and still unclear. Although at least 40 gene
mutations are reportedly associated with noncompaction cardiomyopathy
(e.g., MYH7 and PRDM16 [5-7]), few case reports ofCALM2 mutation in fetal noncompaction cardiomyopathy have been
published. CALM2 is a Ca2+-signaling gene that
encodes for calmodulin and is associated with long QT syndrome (LQTS)
phenotypes. In three reported cases, CALM2 mutation might have
contributed to LQTS accompanied by cardiomyopathy (one case of
hypertrophic
cardiomyopathy and two cases of left
ventricular noncompaction cardiomyopathy),
indicating the variant positions in CALM2(c.396T>G;p.D132E, c.394G>C;p.D132H, and
c395A>G;p.D132G) [8-10]. Our case is the first report
of a novel CALM2 mutation (c.389A>G;p.D130G) in
fetal noncompaction cardiomyopathy
accompanied by bradycardia detected with whole-exome sequencing.
Therefore, we highly suspect that CALM2 is associated with
noncompaction cardiomyopathy, particularly
in fetuses with bradycardia. Sinus bradycardia might be a manifestation
of LQTS in the fetus [11]. Additionally, with reference to
previously reported findings [8-10], we highly suspect thatCALM2 variants might be associated with cardiomyopathy and
arrhythmia, especially LQTS. Nonetheless, further research is required
to confirm this hypothesis and elucidate the pathogenic mechanism.
CONCLUSION
With the improvement of the ultrasonic resolution, the detection rate of
prenatal noncompaction cardiomyopathy was
increased, and it is useful to recognize noncompaction
cardiomyopathy as early as possible.
Meanwhile, this case highlights the importance of genetic testing in the
follow-up of prenatal disease, which will provide human databases with
more information regarding gene defects, mutation sites, and various
phenotypes.