Novel homozygous C3orf67 gene variant associated with primary ciliary dyskinesia in a Saudi pediatric patient: A case report

Abstract

BACKGROUND

Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by motile cilia dysfunction. Identifying pathogenic variants is essential for diagnosis and personalized care, especially in consanguineous populations like Saudi Arabia.

CASE SUMMARY

This report presents a Saudi pediatric patient diagnosed with PCD who exhibited persistent neonatal tachypnea, chronic productive cough, and recurrent otitis media. Whole-exome sequencing revealed a novel homozygous nonsense variant in the C3orf67 gene (NM_198463.2:c.508C>T), resulting in a truncated, non-functional protein. This mutation likely impairs ciliary motility due to the production of a truncated, non-functional protein. The clinical findings were supported by multiple positive sputum cultures and a significant family history of similar symptoms, suggesting a genetic etiology consistent with autosomal recessive inheritance.

CONCLUSION

This case highlights the importance of genetic studies in diagnosing PCD, particularly in communities with a high rate of consanguinity. The identification of a novel homozygous variant in the C3orf67 gene expands the known genetic landscape of the disease. Further research is essential to clarify the functional role of C3orf67 in ciliary biology and its contribution to PCD pathogenesis.

Key Words: Primary ciliary dysfunction; Novel mutation; Pathogenic mutation; C3orf67; Case report

Core Tip: This case report identifies a novel homozygous variant in the C3orf67 gene associated with primary ciliary dyskinesia (PCD) in a Saudi child, expanding the known genetic spectrum of PCD. Through comprehensive clinical evaluation and whole-exome sequencing, this study highlights the importance of genetic testing in early and accurate diagnosis of PCD, particularly in populations with high consanguinity. The findings underscore the need for further research into C3orf67 pathogenic role and reinforce the utility of precision medicine in managing rare ciliopathies.

INTRODUCTION

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by dysfunction of motile cilia, leading to impaired mucociliary clearance and a range of respiratory manifestations including chronic sinusitis, otitis media, and bronchiectasis[1,2]. The disease often presents in the neonatal period with respiratory distress and may be accompanied by situs inversus and congenital heart defects due to defective ciliary function during embryogenesis[3,4]. Although considered rare, with a global prevalence of approximately 1 in 7500 to 1 in 10000 live births, the incidence may be higher in populations with elevated consanguinity rates, such as those in parts of the Middle East[5-7]. PCD is predominantly inherited in an autosomal recessive pattern, though X-linked and autosomal dominant inheritance have also been reported[8]. Advances in molecular diagnostics, particularly whole-exome sequencing, have facilitated the identification of over 50 genes associated with PCD, including dynein axonemal heavy chain 5 (DNAH5), dynein axonemal intermediate chain 1, and radial spoke head 9 homolog (RSPH9), which encode components critical to ciliary structure and motility[5,9,10]. Among Saudi patients, DNAH5 and RSPH9 gene mutations are the most frequently reported; however, the identification of additional genes continues to expand the mutational spectrum and complexity of the disease[6].

The diagnosis of PCD remains challenging due to its phenotypic overlap with other chronic respiratory conditions. As a result, clinical prediction tools such as PCD Rule[11], as well as diagnostic techniques like nasal nitric oxide measurement[12], high-speed video microscopy, transmission electron microscopy, and genetic testing, are critical components of a comprehensive diagnostic workup[13-15]. In this report, we present the case of a Saudi pediatric patient diagnosed with PCD and found to carry a novel homozygous nonsense variant in the C3orf67 gene. This finding contributes to the growing evidence implicating C3orf67 in the pathogenesis of PCD and underscores the importance of genetic testing in populations with a high rate of consanguinity.

CASE PRESENTATION

Chief complaints

A 7-year-old Saudi boy was referred to our facility due to recurrent respiratory infections, chronic wet cough, persistent nasal congestion, and recurrent otitis media since infancy.

History of present illness

Symptoms began in the neonatal period with respiratory distress, tachypnea, and wheezing, leading to multiple hospitalizations for suspected pneumonia. Despite multiple courses of antibiotics, symptoms persisted, with frequent episodes of lower respiratory tract infections requiring hospitalization.

History of past illness

At two years of age, the patient was diagnosed with recurrent otitis media and underwent adenotonsillectomy due to persistent infections. However, he continued to experience frequent purulent ear discharge, indicating ineffective mucociliary clearance. By four years of age, his respiratory symptoms worsened, manifesting as chronic cough, wheezing, and exertional dyspnea, necessitating additional hospitalizations (Table 1).

Table 1 Timeline of disease course and diagnostic interventions.

Age (years)
0	Respiratory distress noted
2	Diagnosed with recurrent otitis media, underwent adenotonsillectomy
4	Exertional dyspnea, chronic cough
7	High-resolution computed tomography, nasal nitric oxide testing, and whole-exome sequencing performed

Personal and family history

Family history was significant for an older sister diagnosed with PCD at the age of 14. She had a complicated clinical course, including a left lower lobectomy due to recurrent pneumonia and severe bronchiectasis. The patient’s mother had also been diagnosed with bronchiectasis and was under pulmonary investigation. Additionally, his three-year-old younger sister had exhibited persistent neonatal tachypnea and chronic wet cough since birth, raising further suspicion of familial PCD (Figure 1).

Figure 1 Family pedigree of the patient - the pedigree highlights affected individuals with a black fill, consanguinity is indicated with a double line, and genotype information is annotated.

Physical examination

Upon examination, the patient appeared well-developed but displayed signs of mild respiratory distress. His weight and height were in the 10^th and 25^th percentiles, respectively. Chest auscultation revealed scattered crepitations and wheezing, with no digital clubbing or severe respiratory distress. Nasal examination revealed no polyps or mucopurulent discharge. Otoscopic examination indicated signs of chronic otitis media without active infection.

Laboratory examinations

Nasal nitric oxide testing, a crucial screening tool for PCD, showed markedly reduced levels (< 77 NL/minute), further supporting the diagnosis. Whole-exome sequencing (Table 2), confirmed the presence of a homozygous pathogenic variant in C3orf67 (NM_198463.2:c.508C>T), leading to a premature stop codon (p.Arginine170*), resulting in a truncated non-functional protein. This variant has been previously identified in association with PCD but remains under-characterized. According to American College of Medical Genetics and Genomics criteria, the C3orf67 variant is classified as likely pathogenic based on population frequency and truncating nature.

Table 2 Molecular genetic testing of the patient (sequence variants).

Gene	Variant coordinate	Amino acid change	SNP identifier	Zygosity	In silico parameters	Allele frequencies	Type and classifications
C3orf67	NM_198463.2:c.508C>T	p.Arginine170*	Rs371569928	Homozygous	PolyPhen: N/A	gnomAD: 0.000016	Nonsense
					Align-GVDG: N/A	ESP: -1000	Likely
					SIFT: N/A	gnomAD: N/A	Affecting
					Mutation taste: N/A	CentoMD: N/A	Protein
					Conservation: Weak		Function
					Conservation: Aa		Class 2P1

¹Class 2P: Pathogenic, class 2 (according to American College of Medical Genetics and Genomics - Association for Molecular Pathology Variant Classification Guidelines variant classification guidelines).

SNP: Single nucleotide polymorphism; PolyPhen: Polymorphism phenotyping; N/A: Not applicable; SIFT: Scale-invariant feature transform; gnomAD: Genome Aggregation Database; ESP: Exome Sequencing Project; Aa: Amino acid; CentoMD: CENTOGENE Mutation Database.

Imaging examinations

A high-resolution computed tomography scan of the chest showed evidence of early bronchiectasis changes in the right middle lobe, mild atelectasis, and peribranchial thickening (Figure 2). Pulmonary function tests revealed normal forced vital capacity and forced expiratory volume in 1 second but a reduced mid-expiratory flow (77%), indicating early-stage small airway disease.

Figure 2 Chest X-ray and computed tomography. A: Atelectatic area at the anterior right middle lobe, visible as increased opacity; B and C: Bronchiectasis in the right middle lobe with mucus plugging and segmental collapse. Shaded areas indicate disease severity.

FINAL DIAGNOSIS

The final diagnosis was PCD.

TREATMENT

Supportive management to slow disease progression including airway clearance, use of mucolytics, and high-frequency chest wall oscillation. Long-term prophylactic antibiotics with regular follow up of pulmonary function. Bronchodilators are used with airway hyperresponsiveness exacerbations. Family counselling regarding the disease and the genetic testing results.

OUTCOME AND FOLLOW-UP

Currently, the patient is on regular follow up and doing well over the past six months.

DISCUSSION

PCD is a rare, genetically heterogeneous disorder affecting ciliary motility, which results in impaired mucociliary clearance and recurrent respiratory infections[1,5]. The clinical spectrum is variable, with patients presenting with neonatal respiratory distress, chronic sinusitis, otitis media, and recurrent pneumonia[2,3,16]. Nearly 50% of affected individuals exhibit situs inversus due to abnormal embryonic left-right axis determination and defective embryonic nodal cilia[1,4,9]. To date, more than 50 pathogenic genes have been implicated in PCD, with mutations affecting dynein arms, radial spokes, and central microtubular structures[5,9,10]. Among Saudi patients, DNAH5 and RSPH9 mutations are the most frequently reported[6], but emerging variants such as C3orf67 suggest additional contributions to disease pathogenesis[7]. The identified mutation in this case (NM_198463.2:c.508C>T) leads to a premature stop codon (p.Arginine170*), predicted to result in a truncated, non-functional protein, thereby impairing normal ciliary structure and motility[10]. The C3orf67 gene, although not fully characterized, is believed to play a structural role in axonemal organization, potentially interacting with radial spoke proteins (UniProt ID: Q8N2E6)[10]. We evaluated the variant as likely pathogenic based on American College of Medical Genetics and Genomics criteria, including its absence from major population databases (gnomAD), truncating nature, and segregation with disease in multiple affected family members[17].

Recent research highlights the critical role of genetic testing in confirming a PCD diagnosis, particularly in consanguineous populations where autosomal recessive inheritance patterns are common[6,7,18]. Advances in genetic technologies, particularly whole-exome and targeted next-generation sequencing, have improved diagnostic accuracy and allowed for the identification of novel variants[5,10,17]. Management of PCD remains largely supportive and aims to prevent disease progression. Standard care includes airway clearance techniques, mucolytics, and high-frequency chest wall oscillation, all of which help improve mucociliary clearance and reduce the frequency of exacerbations[5,13,19]. Long-term antibiotic prophylaxis is frequently employed to suppress chronic infections, and bronchodilators may provide symptomatic relief, especially in patients with airway hyperreactivity[5,13]. Pulmonary function monitoring is essential in tracking disease progression and adjusting treatment[5]. Targeting inflammation has also been proposed as a novel therapeutic approach. Inhaled corticosteroids and leukotriene receptor antagonists have demonstrated some efficacy in reducing airway inflammation and improving respiratory outcomes in selected patients, though their long-term benefit remains under investigation[5,13].

Emerging gene-editing platforms, particularly clustered regularly interspaced short palindromic repeats-based systems, hold promise for correcting underlying genetic defects in ciliopathies such as PCD. Although these techniques are in early experimental phases, studies have shown potential for restoring ciliary function in vitro and in animal models[17,20]. However, clinical application faces several hurdles, including safety concerns, high cost, and limited infrastructure in resource-constrained regions[17,20,21]. This case underscores the importance of incorporating genetic diagnostics into routine PCD evaluation. Early identification of causative variants facilitates personalized treatment, informs family counseling, and opens pathways for research into precision therapies. Continued exploration of genotype-phenotype correlations, functional analysis of novel variants, and therapeutic innovation will be vital in improving long-term outcomes for individuals with PCD[10,20,21].

CONCLUSION

This case highlights the pivotal role of genetic testing in diagnosing PCD and uncovering novel pathogenic variants. The identification of a homozygous C3orf67 variant (NM_198463.2:c.508C>T) expands the known genetic landscape of PCD and underscores the need for further research into its functional impact. Advances in genetic research, precision medicine, and emerging therapies hold promise for improving clinical outcomes and quality of life in individuals with ciliopathies. Future studies should include functional validation of the C3orf67 variant, broader family screenings, and prevalence studies in larger populations.