Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report

Abstract

Ribosomal protein L3-like gene mutations have been implicated in early-onset severe dilated cardiomyopathy (OMIM #115200). This report describes an infant with dilated cardiomyopathy resulting from RPL3L gene mutations. A 2-month-old girl was admitted in June 2022 with poor appetite, breathlessness, and lethargy. Her brother had succumbed to fulminant cardiomyopathy and heart failure at the same age. Cardiac ultrasound revealed an enlarged left ventricle, moderate mitral valve regurgitation, and an ejection fraction of 31%. Chest X-ray revealed cardiac enlargement and pulmonary changes. Cardiac magnetic resonance imaging confirmed dilated cardiomyopathy with an enlarged left ventricle and reduced myocardial wall motion. Whole-exome sequencing identified two RPL3L mutations: c.501G>A (p.Q167=) inherited from the father and c.322G>A (p.E108K) from the mother. Drug therapy improved the patient’s cardiac function, and she demonstrated normal cardiac function after 6 months. In this case, dilated cardiomyopathy was associated with two familial RPL3L gene mutations, consistent with a presumed autosomal recessive inheritance pattern previously described in RPL3L-associated cardiomyopathy.

Introduction

Dilated cardiomyopathy (DCM; OMIM #115200) is a medical condition characterized by an enlarged and weakened heart, which may ultimately result in heart failure. ¹ It arises from primary myocardial disease and is a common cause of heart failure in children. Typical clinical manifestations include left ventricular systolic dysfunction, refractory heart failure, thromboembolism, and sudden death. DCM in children is particularly significant, as the small thoracic cavity can be rapidly overwhelmed by an enlarged heart. ² Furthermore, it is a critical condition and often requires heart transplantation; however, finding a compatible donor heart of the appropriate size for a growing child remains a substantial challenge, and many children die before transplantation. ² DCM is genetically heterogeneous, with more than 100 genes implicated in its pathogenesis. These genes encode proteins involved in diverse subcellular systems, including sarcomeric structure, cytoskeletal integrity, nuclear envelope components, ion channels, mitochondrial function, and ribosomal machinery. ³ Advances in next-generation sequencing have shifted the traditional morphology-based classification of cardiomyopathies toward a molecular and genetic framework. Genetic testing now plays a central role in identifying the underlying etiology, guiding family screening, and informing genetic counseling, particularly in early-onset or familial cases.

Although the pathogenesis of DCM is not completely understood, it involves infectious, genetic, and autoimmune factors. The condition is predominantly associated with genetic mutations that impair myocardial contractile function, resulting in abnormal structural and functional changes to the heart in children. Ribosomal protein L3-like (RPL3L; OMIM #617416) is highly expressed in the heart and skeletal muscles and may contribute to RPL3L-associated DCM, which typically presents in the neonatal period. ⁴ A recent study reported that deletion of the RPL3L gene resulted in reduced heart weight over time. ⁵ Although evidence suggests that mutations in the RPL3L gene may be involved in the development of DCM,^4,6 current data remain limited. Therefore, this report describes the case of an infant with DCM associated with a mutation in the RPL3L gene.

Case report

An approximately 2-month-old girl was admitted to the Pediatric Intensive Care Unit (PICU) of Hainan Women and Children’s Medical Center, Hainan, China, in June 2022 with a half-day history of poor appetite, shortness of breath, and lethargy. She was born at full term without any history of asphyxia or resuscitation and was breastfed. The patient weighed 7.5 kg and was the third child of the couple; the second child had died of fulminant cardiomyopathy, cardiac arrest, and heart failure at 2 months of age. Physical examination revealed a body temperature of 35.9°C, a pulse rate of 197 beats/min, a respiratory rate of 42 breaths/min, and blood pressure of 57/48 mmHg. She appeared drowsy and exhibited generalized skin flushing. Cyanosis of the face and lips was observed, and the inspiratory three-concave sign was positive. Arterial blood gas analysis demonstrated metabolic acidosis (pH < 7.35), hyperoxemia (PO₂ > 100 mmHg), and elevated lactic acid levels (5.9 mmol/L). Routine blood test results revealed a mildly elevated white blood cell count (9.1 × 10⁹/L), low neutrophil percentage (16.6%), low hemoglobin (95 g/L), and normal platelet count (248 × 10⁹/L). Troponin levels were recorded at 96.8 ng/mL and B-type natriuretic peptide (BNP) levels exceeded 25,000 pg/mL. Cardiac ultrasound revealed an enlarged left ventricle, moderate mitral valve regurgitation, and an ejection fraction (EF) of 31% (Figure 1(a) and (b)). Chest X-ray revealed an enlarged cardiac silhouette with pulmonary exudative changes (Figure 1(c)), and electrocardiography showed sinus tachycardia, mild left atrial load, and ST-segment changes (Figure 1(d)). Cardiac magnetic resonance imaging (MRI) revealed left ventricular enlargement and reduced myocardial wall motion, consistent with DCM (Figure 1(e) and (f)). After obtaining written informed consent, whole-exome sequencing (WES) was performed on the patient and her parents, which identified two RPL3L gene mutations: c.501G>A (p.Q167=) synonymous mutation and c.322G>A (p.E108K) missense mutation. Sanger sequencing confirmed that the father carried the c.501G>A mutation, whereas the mother carried the c.322G>A mutation (Figure 2(a) and (b); Figure 3). Family WES analysis indicated the presence of these RPL3L mutations.

Figure 1.

Imaging analysis of patient at the time of admission to the hospital. (a) Cardiac ultrasound with an apical four-chamber view, suggesting a left ventricular enlargement with a reduced amplitude of the left ventricular myocardial wall motion; (b) long-axis view of cardiac ultrasound left ventricular showing the contractile function of the left ventricular myocardial wall, suggesting poor cardiac function and diminished myocardial wall motion; (c) chest radiograph showing a significantly enlarged heart shadow; (d) electrocardiogram showing sinus tachycardia and mid and ST-segment changes in the left atrial load; (e and f) cardiac MR (MRI model: Philips 3TIngenia) on the fifth day of admission. MR: magnetic resonance; MRI: magnetic resonance imaging.

Figure 2.

Whole-exome sequencing analysis. (a) Gene mapping showing that a heterozygous locus c.501G>A (p. Q167=) from the father has a synonymous mutation without a mutation at this locus in the mother; (b) gene mapping showing that a heterozygous locus c.322G>A (p.E108K) from the mother has a missense mutation without a mutation at this locus in the father.

Figure 3.

Family pedigree of the proband. The proband (filled symbol) carries two RPL3L variants: c.322G>A (maternal) and c.501G>A (paternal). The father carried the c.501G>A variant only, and the mother carried the c.322G>A variant only. Other siblings were not genetically tested; the deceased sibling is indicated with a diagonal line and genotype unknown.

According to population databases (gnomAD and the Exome Aggregation Consortium), both RPL3L variants identified in the patient are extremely rare or absent in healthy populations. The missense variant c.322G>A (p.E108K) exhibits a minor allele frequency of 0.0001088, whereas the synonymous variant c.501G>A (p.Q167=) is not reported in population databases. Based on American College of Medical Genetics and Genomics (ACMG) guidelines, ⁷ both variants are classified as variants of uncertain significance (VUS). In silico predictions for c.322G>A are suggestive but not conclusive of pathogenicity, whereas the synonymous variant lacks functional prediction evidence. Segregation analysis confirmed that the father carried the synonymous variant and the mother carried the missense variant, consistent with compound heterozygosity.

After admission, the patient received invasive mechanical ventilation for respiratory support. Dobutamine was administered at a dose of 10 µg/kg/min and maintained for 6 days to support cardiac function. On day 4 of treatment, oral digoxin was initiated using a rapid digitalization protocol, after which dobutamine was discontinued. Subsequent monitoring demonstrated that serum digoxin concentrations remained within the therapeutic range. In addition, sacubitril–valsartan was administered orally at a dose of 1.6 mg/kg per dose twice daily for 14 days. Oral diuretics were prescribed to reduce cardiac preload and alleviate cardiac workload. After transfer from the PICU to the Department of Cardiology, sacubitril–valsartan was discontinued and replaced with oral captopril. The patient’s cardiac function gradually improved, and she was discharged in stable condition. At the 6-month follow-up after discharge, she demonstrated appropriate growth and development. She continued oral digoxin therapy, and serial follow-up assessments confirmed normal cardiac function.

The reporting of this case conforms to the Case Report (CARE) guidelines for case reports. ⁸ We have deidentified all patient details.

Discussion

This case report described an infant with DCM caused by an RPL3L gene defect that was likely familial, supported by a history of a sibling who died at a similar age. The rarity of this gene mutation underscores the importance of expanding genetic testing in neonatal cardiomyopathy.

DCM is a common cause of congestive heart failure. Despite comprehensive cardiovascular evaluation, a specific etiology is often not identified, ⁹ resulting in the classification of the disorder as idiopathic. Endomyocardial biopsy can provide diagnostic and prognostic information in patients with idiopathic DCM; ¹⁰ however, given its invasive nature, the patient’s family declined this examination in the present case. The patient presented with heart failure at onset, with no history of prodromal infection or fever and no arrhythmia during the disease course. Creatine kinase (CK)-MB levels were 20 U/L at admission and were continuously monitored. Screening for common viral infections and autoimmune antibodies associated with myocarditis yielded negative results. Therefore, myocarditis was excluded. Based on the Lake–Louise criteria ¹¹ and MRI findings, ² a diagnosis of DCM was established.

DCM can result from mutations in various genes, including sarcomere-associated, cytoskeleton-associated, nuclear membrane protein–associated, and ion channel–associated genes.^12,13 Mutations in the RPL3L gene are a recognized cause of neonatal DCM, as disruption of ribosomal function ultimately impairs myocardial function.^13,14 In the present case, the patient carried one synonymous RPL3L allele (likely benign, pending confirmation) and one missense allele, suggesting that the missense mutation was pathogenic. The patient carried a missense variant (c.322G>A, p.E108K) inherited from the mother and a synonymous variant (c.501G>A, p.Q167=) inherited from the father. The pathogenicity of the synonymous variant is currently uncertain, as no functional evidence supports its contribution to disease. Therefore, the observed phenotype is most likely attributable to the missense variant in the context of a compound heterozygous autosomal recessive inheritance pattern, consistent with previously reported RPL3L-associated neonatal DCM.^15,16 RPL3L, located on the long arm of human chromosome 16, is primarily involved in encoding components of the nuclear membrane and shares 77% homology with the ribosomal protein gene. ¹⁷ Ribosomes, as central elements of protein synthesis, are essential for the growth and fusion of myoblasts and play a critical role in development. ¹⁸ RPL3L is a homologue of RPL3, a highly conserved ribosomal protein that forms part of the 60S ribosomal subunit, ¹⁹ and contributes to the ribosomal peptidyl transferase center, coordinating function as the gatekeeper of the ribosomal A-site. It is widely expressed throughout the body.

This case highlights the importance of early WES in pediatric cardiomyopathy to enable timely identification and management of genetic disorders. In the patient case, WES revealed two RPL3L gene mutations, c.501G>A (p.Q167=) and c.322G>A (p.E108K). RPL3L mutations at different loci, including c.724C>T (p.R242W), c.923A>T, and c.1027C>T, have been reported.^14,15 Mutations in the RPL3L gene have also been reported in other studies. For example, biallelic missense mutations in RPL3L were identified in seven patients from different families with severe early-onset familial DCM, none of whom exhibited coronary heart disease, valvular disease, or arrhythmia; only two survived following heart transplantation. ⁶ These findings indicate that RPL3L mutations are rare in the general population and are associated with severe, acute, decompensated infantile DCM.

This study is limited by the absence of functional assays to directly assess the impact of the identified RPL3L variants (c.322G>A and c.501G>A) on protein function or cardiomyocyte physiology. Functional studies, such as in vitro expression, ribosome biogenesis assays, or cardiac model systems, would provide stronger evidence for pathogenicity and may help reclassify the variants from uncertain significance to likely pathogenic or benign. Therefore, our interpretation of the genotype–phenotype correlation relies primarily on clinical presentation, segregation analysis, and population frequency data. Future studies incorporating functional characterization are warranted to better define the role of these RPL3L variants in neonatal DCM.

Conclusion

This case expands the clinical spectrum of RPL3L-associated infantile DCM and supports an autosomal recessive inheritance pattern resulting from compound heterozygous variants. Early application of WES in infants presenting with unexplained severe cardiomyopathy may facilitate timely genetic diagnosis, guide family counseling, and inform recurrence risk assessment. Given the limited number of reported cases, further functional studies and long-term follow-up are warranted to clarify genotype–phenotype correlations and optimize management strategies for affected patients.