Introduction
Dilated cardiomyopathy in childhood represents a heterogeneous group of disorders with genetic, infectious, and metabolic aetiologies. Variants in genes such as TTN, LMNA, and MYH7 account for a substantial proportion of cases; however, the underlying cause remains unidentified in a subset of patients. Reference Andersson, Schou and Schwartz1,Reference Herman, Lam and Taylor2
Recent evidence suggests that genes not traditionally associated with cardiomyopathy may also contribute to myocardial dysfunction. COL5A1 , the major disease gene for classical Ehlers–Danlos syndrome, has been associated with cardiovascular manifestations, including aortic disease and valvular abnormalities, although its direct role in dilated cardiomyopathy remains uncertain and is supported mainly by limited case-based evidence. Reference Zainal, Hamad and Naqvi3,Reference Mansoorshahi, Yetman and Bissell4 Likewise, ABCC9 has been associated with dilated cardiomyopathy, although current evidence supporting a causal role remains limited. Reference Herman, Lam and Taylor2,Reference Semsei, Erdelyi and Ungvari5,Reference Yag, Li and Yang6
Here, we report a child with early-onset severe dilated cardiomyopathy harbouring variants in both COL5A1 and ABCC9 . This case expands the clinical spectrum associated with these genes and raises the possibility of a complex genetic contribution to the severity of the phenotype.
Case presentation
A previously healthy 16-month-old boy was admitted with progressive respiratory distress of several weeks’ duration. On physical examination, he had generalised oedema but remained haemodynamically stable. Chest radiography demonstrated pulmonary oedema. Laboratory evaluation revealed mildly elevated troponin levels without a dynamic rise, and there were no clinical or laboratory findings suggestive of myocarditis.
Transthoracic echocardiography revealed marked dilation of the left-sided cardiac chambers and severely reduced systolic function, with an estimated ejection fraction of approximately 30% (Figure 1, Supplementary Video 1). No structural heart disease was identified. Holter monitoring did not reveal any arrhythmia.
Apical four-chamber view demonstrating marked dilation of the left-sided cardiac chambers (left atrium and left ventricle) with severely reduced systolic function.
The patient was treated with inotropic support, diuretics, and antiplatelet therapy. Despite intensive treatment, ventricular function remained significantly impaired.
Cardiac MRI confirmed a non-ischaemic dilated cardiomyopathy phenotype. Left ventricular volumes were increased, ejection fraction was reduced (approximately 27%), and no late gadolinium enhancement or evidence of myocardial fibrosis was observed.
As part of the aetiological evaluation, metabolic investigations were performed to assess for inborn errors of metabolism associated with dilated cardiomyopathy, and no findings suggestive of a metabolic disorder were identified. Genetic analysis was subsequently performed using clinical exome sequencing targeting genes associated with cardiomyopathy and connective tissue disorders. Clinical exome sequencing identified a heterozygous likely pathogenic variant in ABCC9 (NM_020297:c.2072T>A; p. Ile691Lys) and a heterozygous variant of uncertain significance in COL5A1 (NM_000093:c.3812C>T; p. Pro1271Leu). Variant classification was performed according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines and interpreted in the context of the patient’s clinical phenotype. Despite the identification of the COL5A1 variant, the patient had no clinical features suggestive of classical Ehlers–Danlos syndrome, including joint hypermobility, skin hyperextensibility, easy bruising, or abnormal scarring. Parental segregation analysis was recommended; however, the family did not consent to additional genetic testing, and therefore the inheritance pattern of either variant could not be determined.
At the 9-month follow-up, partial improvement in left ventricular systolic function was observed, with an ejection fraction of 47% and fractional shortening of 23%. The left ventricular end-diastolic and end-systolic diameters were 3.7 cm and 2.8 cm, respectively. In view of the improvement in ventricular function and clinical status, heart transplantation was deferred. The patient continues to be followed in the outpatient clinic.
Discussion
This case describes early-onset severe dilated cardiomyopathy in an infant harbouring variants in both COL5A1 and ABCC9. The coexistence of these variants raises the possibility of a complex genetic contribution to the unusually early and severe phenotype.
COL5A1 encodes the α1 chain of type V collagen, an essential component of the extracellular matrix. Pathogenic variants in COL5A1 are the major cause of classical Ehlers–Danlos syndrome, in which cardiovascular manifestations, including aortic dilation and valvular abnormalities, have been reported. However, myocardial involvement is uncommon, and the association between COL5A1 variants and dilated cardiomyopathy is supported mainly by isolated case reports. Reference Zainal, Hamad and Naqvi3,Reference Mansoorshahi, Yetman and Bissell4,Reference Butler7
Published reports of COL5A1-associated myocardial dysfunction predominantly involve adults, and early-onset severe dilated cardiomyopathy in children has not been well characterised. This case therefore adds to the limited literature on the potential myocardial manifestations of COL5A1 variants.
ABCC9 has been implicated in dilated cardiomyopathy, although current evidence supporting a causal role remains limited. Available evidence suggests that it may modify susceptibility to myocardial injury and disease progression rather than acting as a primary cause of cardiomyopathy, and its contribution to idiopathic dilated cardiomyopathy remains uncertain. Reference Herman, Lam and Taylor2,Reference Semsei, Erdelyi and Ungvari5,Reference Yag, Li and Yang6,Reference Valcovici, Andrica, Serban and Dragan8
Although the likely pathogenic ABCC9 variant may explain part of the cardiac phenotype, it may not fully account for the unusually early onset and marked disease severity. The accompanying COL5A1 variant, although classified as a variant of uncertain significance, raises the possibility of an additional contribution to disease expression. Although a causal relationship cannot be established from a single case, the unusually early onset, marked disease severity, and absence of alternative aetiologies raise the possibility that the coexistence of these variants contributed to the phenotype. A structural predisposition related to extracellular matrix dysfunction, together with altered myocardial stress responses, may have increased myocardial vulnerability, suggesting that multiple genetic factors rather than a single variant may have influenced disease expression.
This case highlights the importance of interpreting genetic findings within the clinical context and considering the potential contribution of multiple genetic variants in paediatric cardiomyopathy. A limitation of this report is the lack of parental segregation analysis, as the family did not consent to additional genetic testing; consequently, whether either variant was inherited or occurred de novo remains unknown.
Conclusion
This case suggests that a likely pathogenic ABCC9 variant together with a COL5A1 variant may have contributed to an unusually early and severe dilated cardiomyopathy phenotype.
Further studies are needed to clarify the potential contribution of multiple genetic variants to disease expression in paediatric cardiomyopathy.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S1047951126124809.
Data availability statement
The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Author contribution
H.E.B. contributed to the conception and design of the study, patient management, data collection, data interpretation, and manuscript drafting. H.T. contributed to critical revision of the manuscript. Both authors read and approved the final manuscript.
Financial support
No funding was received for this study.
Competing interests
The authors declare no competing interests.
Ethical standard
The authors declare that the research presented in this manuscript adheres to the ethical principles outlined by the institutional review board of Erzurum City Hospital. All procedures involving human participants were conducted in accordance with the ethical standards of the institution and the Declaration of Helsinki (1964), as revised in 2013. According to institutional policy, ethical approval was not required for single case reports.
Informed consent
Written informed consent was obtained from the patient’s parents for publication of this case report.
