Dilated cardiomyopathy is a heterogeneous disease and the most common type of cardiomyopathy in children. Although most cases are classified as idiopathic, a specific genetic variant has been identified in 35% of patients with dilated cardiomyopathy. Reference Kindel, Miller and Gupta1 Dispatched RND transporter family member 1 mutation has been previously only reported in association with microcephaly, developmental delay, and other midline facial defects. Reference Kantarci, Ackerman and Russell2 We present a novel case report of a patient with dilated cardiomyopathy with a genetic variant in dispatched RND transporter family member 1.
Case presentation
Our case was a 3-year-old female previously diagnosed with developmental delay, milestones regression, microcephaly, and strabismus. She underwent extensive genetic evaluation and was found to have a dispatched RND transporter family member 1 gene mutation at 12 months of age. She later presented at 3 years of age to the emergency department after becoming unresponsive at home. Initial resuscitation revealed severe bradycardia with severely depressed left ventricular function, requiring transcutaneous pacing and later emergent temporary transvenous pacemaker implantation due to hemodynamic instability. Her baseline electrocardiogram revealed bradycardia with junctional escape rhythm (Fig 1).
Figure 1. Initial electrocardiogram demonstrating bradycardia with junctional escape rhythm.
Her initial echocardiogram exhibited severely dilated left ventricular with severely depressed left ventricular systolic function. (Ejection fraction: 35.2%; Shortening fraction: 16.7%) (Fig 2)
Figure 2. Initial echocardiogram demonstrating severe left ventricular dilation with moderate mitral valve regurgitation.
After several days of stabilisation, we decided to proceed with permanent epicardial pacemaker implantation because of pacemaker dependency. Her echocardiogram at discharge showed minimal improvement with moderate left ventricular dilation and moderate decreased left ventricular function. In addition, at discharge she was pacemaker-dependent with 100% atrial and ventricular pacing. During her subsequent follow-up in the outpatient setting, she remains with similar left ventricular dilation and function and pacemaker dependency.
Family history revealed that her parents are first cousins and our patient has 4 healthy siblings. Interestingly, our patient had two maternal cousins with global developmental delay who died at a very young age. One of them was diagnosed with long QT syndrome as an infant and required pacemaker implantation at 18 months of age and died suddenly at 12 years of age due to cardiac arrest. The other maternal cousin presented to the hospital after a possible “seizure episode” and died at 18 months of age. Regarding our patient’s past medical history, she was born full-term and she was developing appropriately until 6 months of age when she started developing amblyopia, global hypotonia with regression of developmental milestones, and loss of motor skills. Her genetic evaluation included an array comparative genomic hybridisation analysis that showed the absence of heterozygosity consistent with her parental consanguinity. We performed a comprehensive cardiomyopathy and cardiac arrhythmia panel with non-diagnostic results. A microcephaly sequencing panel found a maternally inherited dispatched RND transporter family member 1 variant of unclear clinical significance (c.2477G > A). Mitochondrial genome sequencing and whole exome sequencing were normal other than the previously identified dispatched RND transporter family member 1 variant. She also had an electrocardiogram, echocardiogram, and Holter monitor that showed normal results at 12 months of age.
Discussion
Although specific pathogenic gene variants can be identified in up to 20–35% of patients with dilated cardiomyopathy, majority of cases are designated as idiopathic. Reference Kindel, Miller and Gupta1,Reference Paldino, De Angelis and Merlo3 In recent years, widespread use of comprehensive genetic analysis has identified a wider spectrum of pathogenic genes in dilated cardiomyopathy. Dispatched RND transporter family member 1 encodes a transmembrane dispatched RND transporter family member protein that is involved in regulating the release of cholesterol and palmitoyl modified hedgehog proteins. Reference Kantarci, Ackerman and Russell2 Its protein products are required for normal Hedgehog signalling pathway which is necessary for the development of the coronary vasculature in the embryonic heart, and it is also involved in the formation of new coronary vessels in the adult heart. It has also described that the Hedgehog pathway is associated with cardiac repair and regeneration. Reference Wang, Lu, Zhao and Sheng4 There are previous reports of dispatched RND transporter family member 1 mutation in families associated with developmental delay, seizures, microcephaly, and other midline facial defects. Recent studies have also proposed dispatched RND transporter family member 1 as a congenital diaphragmatic hernia candidate gene, due to the association of complex congenital diaphragmatic hernia with de novo dispatched RND transporter family member 1 point mutation and extensive embryonic mouse diaphragm and lung tissue expression. Reference Kantarci, Ackerman and Russell2,Reference Jun, Hur and Lee5 There are no reports of patients with dispatched RND transporter family member 1 mutation and cardiac anomalies.
Our patient underwent comprehensive genetic evaluation. A whole exome sequence analysis for our patient along with maternal and paternal samples revealed regions of homozygosity identified on the chromosomal microarray consistent with history of consanguinity. Furthermore, she is heterozygous for a novel variant in the dispatched RND transporter family member 1 gene, present also in her mother, who has normal phenotype. Her maternal family history was also significant for multiple members with a history of seizure, developmental delay, sudden death, and microcephaly.
Recently in July 2021, the American College of Medical Genetics revised its guidelines for the evaluation of infantile patients with congenital anomalies, suggesting that whole exome sequence, rather than targeted gene panels, should be pursued as first-line testing or second-line testing after chromosomal microarray unless there is a clearly defined syndrome to direct targeted testing. Reference Manickam6 Hereditary cardiomyopathies have substantial phenotypic and molecular complexity for which broader-based molecular testing strategies, such as chromosomal microarray and whole exome sequence, may be more useful as first-line testing, rather than broad-based cardiomyopathy gene panels which can vary in coverage based on the company who developed the panel. Patients with novel pathogenic variants which have been poorly described thus may be at increased risk for delayed diagnosis and ultimately possible interventions that could affect their prognosis.
Conclusion
In summary, we report a novel case of a female patient with dilated cardiomyopathy, microcephaly, and familial consanguinity with a genotype including a maternally inherited genetic variant in dispatched RND transporter family member 1 with significant loss of heterozygosity. As hereditary cardiomyopathies have a substantial phenotypic and molecular complexity making genetic testing challenging, we suggest that broad-based testing genetic testing modalities, such as chromosomal microarray and whole exome sequence rather than targeted gene panels based on broad cardiomyopathy phenotypes, should be pursued as first-line testing to evaluate children with features strongly suggestive of cardiogenetic syndromes. This strategy includes including clarifying variants in dilated cardiomyopathy-related genes, such as dispatched RND transporter family member 1, as they continue to be reported in the future. Our case may help support the need for long-term management and monitoring for patients with dilated cardiomyopathy who hold genetic variants in dispatched RND transporter family member 1.
Acknowledgements
None.
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of interest
The authors declared no potential conflicts of interest
