CCDC39 Mutation-Related Primary Ciliary Dyskinesia with Congenitally Corrected Transposition of the Great Arteries: A Case Report

Introduction

Primary ciliary dyskinesia (PCD) is a fairly uncommon genetically heterogeneous condition that results from structural and functional defects of motile cilia. These small, hair-like organelles are essential for maintaining mucociliary clearance in the respiratory tract and for establishing left-right symmetry during embryogenesis [1]. Dysfunctional motile cilia in PCD result in defective mucociliary transport, which clinically presents with recurrent respiratory infections, chronic sinusitis, otitis media, bronchiectasis, and, in some instances, infertility and laterality defects, including situs inversus and heterotaxy [2–4].

The disorder has an autosomal recessive inheritance pattern and an approximate incidence of 1 in 10 000 to 1 in 20 000 live births. However, this is likely underestimated due to diagnostic challenges, particularly in individuals without classic manifestations, such as situs anomalies or neonatal respiratory distress [1,4,5]. Cilia ultrastructure is highly conserved and usually demonstrates a “9+2” microtubule arrangement in motile cilia, with 9 peripheral doublets surrounding a central pair. Efficient motility requires the coordinated molecular motor activity of outer dynein arms, inner dynein arms (IDAs), radial spokes, and the nexin-dynein regulatory complex. Impaired or irregular movement of cilia can result from genetic mutations in these structural or regulatory components [6].

The CCDC39 gene is essential to the structural integrity and coordinated movement of cilia. CCDC39 mutations are reported to cause a severe form of PCD. They are associated with a combination of IDA and nexin-dynein regulatory complex defects, resulting in microtubular disorganization in the ciliary axoneme. Such structural abnormalities lead to stiff, hyperkinetic, and poorly coordinated ciliary motion, which disrupts normal ciliary function [6,7]. Moreover, CCDC39 is associated with more severe pulmonary involvement, including consolidation of multiple lung lobes and impaired growth parameters, compared with other genes responsible for PCD [8,9]. In this case, we report a novel homozygous nonsense mutation in CCDC39 leading to a truncated, non-functional protein, consistent with a severe PCD phenotype.

Motile cilia are essential for mucociliary clearance in the mucosal layer of the respiratory tract and are crucial in defining left-right asymmetry during embryogenesis. This is achieved by a specific set of motile cilia in the embryonic node, which produce directional fluid flow that signals proper organ alignment. When ciliary motility is compromised, as in PCD due to CCDC39 mutations, directional flow is disturbed, resulting in randomization or abnormal placement of visceral organs, a general malformative process known as laterality defects. Among these defects, heterotaxy is a spectrum of abnormal left-right patterning, ranging from simple to complex congenital heart malformations. One of the malformations is congenitally corrected transposition of the great arteries (ccTGA) [10,11], an uncommon cardiac anomaly characterized by discordant atrioventricular and ventriculo-arterial connections, yet with physiologically correct blood flow typically associated with anatomic and conduction abnormalities [12].

Our case involves a particularly infrequent cardiovascular manifestation – ccTGA – a complex cardiac anomaly not commonly associated with CCDC39-related PCD. This observation contributes to the phenotypic spectrum associated with CCDC39 mutations and underscores the importance of heightened clinical awareness.

Case Report

We report a case of a female infant born at 38 weeks of gestation via an uncomplicated vaginal delivery to consanguineous Saudi parents. The 26-year-old mother had consistent antenatal care during which fetal echocardiography identified multiple congenital anomalies, including ccTGA, dextrocardia with mirror-image atrial arrangement, a significant ventricular septal defect, and abdominal situs inversus, with a right-sided stomach and midline liver. A family history was notable for a sibling with a chronic wet cough and dextrocardia with situs inversus totalis, who was under investigation for a possible diagnosis of PCD.

Following delivery, the neonate was transferred directly to the Neonatal Intensive Care Unit for evaluation and treatment of the known cardiac anomalies. A chest X-ray confirmed the presence of situs inversus totalis with dextrocardia (Figure 1), raising concerns about an underlying laterality defect. Transthoracic echocardiography further delineated the cardiac anatomy, revealing ccTGA characterized by a D-looped ventricle and flow acceleration across the pulmonary valve. A large outlet ventricular septal defect and moderate tricuspid regurgitation were also identified (Figure 2). The patient was initiated on supplemental oxygen therapy to maintain a saturation level above 95%, with an FiO2 range of 21% to 30%.

The patient was given a diagnosis of ccTGA, which differs from D-transposition of the great arteries. A key distinction is that ccTGA typically does not cause cyanosis and often does not require immediate surgical intervention. While the patient showed promising stabilization after birth, the presence of a large ventricular septal defect, moderate tricuspid regurgitation, and ongoing respiratory symptoms prompted the medical team to postpone surgery for further careful evaluation. This thoughtful decision was made in collaboration with the family involved, reflecting our commitment to providing the best possible care.

On day 5 of life, the infant developed copious respiratory secretions necessitating frequent suctioning. A pediatric pulmonology consultation was sought due to concerns regarding potential primary pulmonary pathology. Although there was no formal evaluation of ciliary ultrastructure, the combination of laterality defects and persistent respiratory instability raised clinical suspicion for ciliopathy, particularly PCD. By day 20, the patient’s respiratory status had improved, and she was successfully weaned off nasal cannula oxygen support, maintaining oxygen saturations above 90%. She was discharged on day 23 in stable condition, with a regimen that included hypertonic saline nebulization and follow-up with cardiology and pulmonology services. Initial pulmonary assessments raised suspicion of PCD, owing to unexplained respiratory distress and excessive secretions that could not be attributed solely to ccTGA. Although our center did not have access to nasal nitric oxide testing and electron microscopy, we did send genetic testing (whole-exome sequencing) early in the patient’s admission. However, the results usually take about 3 months to obtain. In the meantime, the patient showed some improvement and was discharged with plans for outpatient follow-up.

At 1 month of age, the infant was readmitted with symptoms of fever, increased respiratory effort, and vomiting. Pneumonia was diagnosed, and she was commenced on intravenous antibiotics. During this admission, she experienced recurrent right lung collapse and required intermittent respiratory support via high-flow nasal cannula and continuous positive airway pressure. Given the recurrent pulmonary symptoms, early-onset respiratory distress, situs abnormalities, and a suggestive family history, a differential diagnosis including cystic fibrosis, immunodeficiency, and PCD were considered. Cystic fibrosis was ruled out based on negative newborn screening and clinical profile, and immunodeficiency screening was unremarkable. Based on these findings, a diagnosis of PCD became increasingly likely, and whole-exome sequencing was pursued, which further revealed homozygous pathogenic variants in the CCDC39 gene, confirming the diagnosis of PCD.

In the present case, whole-exome sequencing identified a homozygous pathogenic frameshift variant in the CCDC39 gene c.2230_2233del (p.Gln744Aspfs*17), which results in a premature stop codon and likely leads to nonsense-mediated mRNA decay. Both parents were confirmed to be heterozygous carriers, consistent with autosomal recessive inheritance, and the same variant was found to be homozygous in an affected sibling (Figure 3). The CCDC39 variant c.2230_2233del (p.Gln744Aspfs*17) is a previously unreported frameshift mutation predicted to cause loss of function, a known disease mechanism for CCDC39. It meets American College of Medical Genetics and Genomics criteria for likely pathogenicity, is extremely rare, with an approximate allele frequency of 0.0015% in gnomAD, and is absent in homozygous controls. Its segregation in the family and the patient’s phenotype further support its pathogenic classification [13].

At 4 months of age, the patient was referred to a tertiary cardiac center for advanced evaluation. However, owing to the complexity of the cardiac anatomy and the child’s fragile status, compounded by recurrent respiratory infections and a confirmed diagnosis of PCD, surgical correction was deemed high risk by a multidisciplinary team including pediatric cardiologists, pulmonologists, intensivists, and geneticists. The patient continued to receive conservative management, including airway clearance therapies (salbutamol nebulization, 3% hypertonic saline, and chest physiotherapy), and medical treatment for heart failure. Despite comprehensive care, the infant had cardiopulmonary arrest secondary to sepsis and died shortly thereafter.

Discussion

CCDC39 mutations are typically associated with IDA defects and microtubular disorganization (MTD), resulting in more severe respiratory phenotypes. However, associations with complex laterality defects, especially ccTGA, have not been previously reported in CCDC39-related PCD. No study has revealed the association between the CCDC39 mutation and ccTGA. However, there is a strong mechanistic and clinical association between CCDC39-related PCD and the development of laterality defects, which often include complex congenital heart diseases. CCDC39 is crucial for the assembly of IDAs and the nexin-dynein regulatory complex, which are essential for the structural integrity and motility of cilia [8]. Dysfunctional motile cilia, especially in the embryonic node, disrupt the normal leftward flow required for correct left-right axis specification in embryonic development. This disruption can cause heterotaxy syndromes with unusual orientation of thoracic and abdominal organs, and often with congenital heart defects. Although ccTGA is not directly mentioned in the literature as a direct consequence of CCDC39 mutations, it is one of the recognized manifestations on the spectrum of heterotaxy-associated cardiac malformations [14,15]. Thus, the presence of ccTGA in the present patient with a confirmed CCDC39 mutation likely reflects the broader impact of ciliary dysfunction on cardiac morphogenesis, reinforcing the clinical relevance of comprehensive genetic and cardiac evaluation in suspected PCD cases.

Laterality defects occur in approximately 50% of patients with PCD and can range from situs inversus totalis to more complex anomalies classified as situs ambiguus or heterotaxy [5,16]. According to Shapiro et al, heterotaxy represents a subset of situs ambiguus characterized by abnormal organ positioning combined with complex congenital heart defects. Mutations affecting the outer dynein arms, such as those in DNAH5, have been more commonly associated with heterotaxy and severe cardiac anomalies [16,17]. Recent data suggest that IDA/MTD defects, such as those caused by CCDC39 mutations, do not typically lead to heterotaxy or cardiac malformations [18]. Interestingly, however, our patient presented with ccTGA (a form of heterotaxy) despite having an IDA/MTD-related CCDC39 mutation. Although a retrospective multicenter study of 559 patients with PCD found no cases of heterotaxy among those with confirmed IDA/MTD defects [18], the present case suggests that such associations, while rare, can occur. These findings suggest that such genotype-phenotype correlations are broader than previously recognized. Similarly, a previous report describing twins with PCD and ccTGA, with differing situs arrangements, further supports the possibility that genetic and non-genetic factors contribute to laterality outcomes [19].

The relationship between CCDC39-associated PCD and ccTGA can therefore be explained by this developmental pathway. CCDC39 mutations disrupt the function of nodal cilia during embryogenesis, thereby impairing mechanisms that set up the body’s left-right axis. This dysfunction makes affected individuals susceptible not only to situs inversus/situs ambiguus but also to heterotaxy syndromes that involve complex heart defects, such as ccTGA. The combined occurrence of PCD and heterotaxy, especially in patients with CCDC39 mutations, is relatively uncommon [15,17], highlighting the importance of genetic assessment in PCD patients with congenital heart disease and the need for early identification, which can inform clinical surveillance and management.

Conclusions

This case represents the first reported association between a novel, pathogenic homozygous CCDC39 frameshift mutation and ccTGA, a rare and complex congenital heart defect. The unusual co-occurrence of a novel CCDC39 variant and ccTGA expands the phenotypic spectrum of IDA/MTD-related PCD, challenging assumptions about the relationship between specific ciliary ultrastructural defects and laterality outcomes. The patient’s dual diagnosis of genetically confirmed PCD and ccTGA posed significant management challenges. Early surgical correction of the cardiac defect was deferred owing to the infant’s clinical fragility, recurrent infections, and overall instability, which may have stemmed from undiagnosed PCD, among other contributing factors. A multidisciplinary team concluded that surgical risks outweighed potential benefits in this context, leading to a conservative approach centred on pulmonary care and heart failure management. This case underscores the diagnostic value of early genetic testing in neonates with situs abnormalities and unexplained respiratory distress. Prompt identification of ciliopathy-related disorders, like PCD, can facilitate timely interventions and inform multidisciplinary decision-making. Further research is needed to clarify these genotype-phenotype correlations, ideally incorporating genetic and ultrastructural analyses.