B47-33 Genetic Testing Reveals What Clinical Assumptions Miss: Undiagnosed Primary Ciliary Dyskinesia in a Puerto Rican Founder Population

Abstract Introduction Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder caused by pathogenic variants in genes essential for motile cilia structure and function. Defective ciliary motility impairs mucociliary clearance, leading to neonatal respiratory distress, chronic wet cough, recurrent sinusitis and otitis media, and progressive bronchiectasis. Approximately half of patients have situs inversus, and some experience infertility from immotile sperm or fallopian tube cilia. A definitive diagnosis is established based on at least one characteristic clinical feature plus a positive result from genetic testing and/or transmission electron microscopy (TEM). Mutations in RSPH4A, encoding a radial spoke head protein, cause a distinct phenotype often lacking laterality defects or infertility. In Puerto Rican populations, a founder pathogenic variant (RSPH4A c. 921 + 3₆delAAGT) accounts for most molecularly confirmed cases. Despite this well-established founder effect, underrecognition remains common, leading to diagnostic delays until advanced lung disease develops. Case description A 40-year-old Puerto Rican male presented with severe, recurrent bronchiectasis and 4-5 annual hospitalizations for infectious exacerbations. His computed tomography (CT) scan showed cystic bronchiectasis, and spirometry demonstrated a severe obstructive ventilatory defect with air trapping and no significant bronchodilator response. He had been treated for years as having COPD without prior PCD evaluation, despite a sister with genetically confirmed PCD who underwent lung transplantation in 2012. Genetic testing revealed homozygosity for the RSPH4A c. 921 + 3₆delAAGT, confirming PCD. He had two biological children, and cascade testing demonstrated both were heterozygous carriers of the RSPH4A variant and also heterozygous for a DNAH5 mutation inherited from their mother, who reported lifelong sinusitis without significant pulmonary disease. The daughter had childhood sinusitis but is currently asymptomatic. Discussion This case highlights how genetic testing can uncover overlooked heritable disease within a founder population and overturn years of misdiagnosis. The patient’s preserved fertility could have falsely reassured clinicians, yet RSPH4A-related PCD often preserves sperm motility due to intact central microtubular structure. Awareness of the Puerto Rican RSPH4A founder variant enables rapid, cost-effective molecular confirmation, guiding airway clearance therapy, infection prevention, and family counseling. Early diagnosis is critical to slowing bronchiectasis progression and reducing need for lung transplantation. As approximately 30% of PCD cases exhibit normal or non-diagnostic ciliary ultrastructure on TEM, reliance solely on ultrastructural findings may yield false negatives. Genetic testing is more accessible and provides higher diagnostic yield than TEM. Integrating genetic testing into diagnostic algorithms offers a more reliable and equitable approach that can fundamentally improve outcomes for PCD patients. This abstract is funded by: None