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Overcoming Diagnostic Challenges in Primary Ciliary Dyskinesia: A Case Report on the Utility of Long-Read Sequencing for Detecting HYDIN Variants 

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction
Primary ciliary dyskinesia (PCD) is a genetic disorder that impairs the structure and function of cilia, causing mucus and bacterial buildup in the respiratory tract. This leads to recurrent nasal congestion, sinus infections, and otitis media. Although several genes have been identified in PCD pathology, 20-30% of clinically diagnosed individuals lack identifiable genetic mutations. The HYDIN gene has been associated with autosomal recessive PCD.  However, it’s pseudogene (HYDIN2) with high similarity (98% identical in 79 of HYDIN’s 86 exons) presents significant diagnostic challenges as current genetic tests cannot reliably identify or validate variants due to this homology.

Case Presentation
A 43-year-old female with a clinical diagnosis of PCD presented with a history of respiratory issues beginning at birth, including recurrent sinusitis, pneumonia, and otitis media, requiring ear tube placement, as well as bronchiectasis. Initial evaluations, including a sweat chloride test, were negative. At age 6, endobronchial biopsy findings on electron microscopy indicated structural airway defects, leading to a PCD diagnosis. Throughout adolescence, the patient had multiple courses of antibiotic treatment. By age 24, she had been hospitalized with pneumonia, and  experienced worsening pulmonary symptoms, including hemoptysis, alongside declining pulmonary function.

 

Diagnostic Workup
The patient's diagnostic workup included pulmonary function tests that revealed below-normal values, including FEV1 and FEV1/FVC ratio suggestive of obstruction, commonly associated with PCD. Her nasal nitric oxide levels were low (26 ppb, reference: 77 ppb). Attempts to identify genetic causes by short-read genome sequencing (srGS) resulted in detection of two pathogenic HYDIN variants (p.Gln1806Ter and c.3786-1G>T) that could not be clinically validated due to the pseudogene overlap. Phasing of these variants was also not possible due to the lack of parental samples. There were no pathogenic variants in other known PCD- or bronchiectasis-related genes including CFTR.

Treatment and Management
Throughout her life, the patient received treatments for chronic sinusitis, including sinus surgery and stent placement. She also required a chest tube for parapneumonic effusion management during a pneumonia episode and received supportive care for her pulmonary symptoms.

 

Outcome and Follow-Up
The patient continued to experience chronic respiratory issues and progressive lung function decline, indicative of the ongoing challenges in managing her PCD symptoms. Her genetic diagnosis was resolved by HiFi long read sequencing (lrGS). lrGS not only allowed unambiguous detection of two pathogenic variants in HYDIN, it also phased variants from the proband sample and confirm a compound heterozygous configuration.

 

Discussion
This case highlights the challenges in identifying a molecular diagnosis in individuals with PCD, particularly for patients with suspected pathogenic variants in HYDIN. The presence of the HYDIN2 pseudogene complicates alignment and detection of variants in HYDIN , which may contribute to the underdiagnosis of HYDIN-related PCD cases. srGS struggles with accurately detecting and validating HYDIN variants, leading to diagnostic gaps. lrGS, however, successfully identified and phased two pathogenic HYDIN variants in this patient, illustrating the value of this approach in overcoming pseudogene challenges.

 

Conclusion
This case emphasizes the utility of lrGS in diagnosing HYDIN-related PCD, as it allows for accurate variant detection and phasing despite pseudogene interference. Implementing long-read sequencing could improve diagnostic accuracy in PCD patients, particularly those with unresolved genetic findings in HYDIN, thereby offering potential for more precise management, monitoring of the disease and more accurate genetic counseling regarding recurrence risks.

 

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